Reversible oxidation of protein tyrosine phosphatases

ABSTRACT

The invention relates to a method of identifying any protein tyrosine phosphatase (PTP) that undergoes reversible modification of PTP active site invariant cysteine within a cell, such that the phosphatase is transiently protected from irreversible active site invariant cysteine-directed PTP inactivating agents. Methods related to regulation of PTPs by reactive oxygen species (ROS) in a cellular environment are provided. Multiple PTPs are shown to be reversibly oxidized and inactivated following treatment of cells with H 2 O 2  or with physiological stimuli that promote ROS formation, and inhibition of PTP function is shown to contribute to ROS-induced mitogenesis. Transient oxidation of the PTP catalytic site invariant cysteine is exploited in methods to identify which of multiple candidate PTPs are components of a given biological signal transduction pathway, without a requirement for first specifically purifying any particular candidate PTP.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 60/356,810 filed Feb. 13, 2002, which is incorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENT INTEREST

[0002] The United States government may have certain rights in this invention under grant number R01-GM55989 from the National Institutes of Health.

BACKGROUND OF THE INVENTION

[0003] The present invention relates generally to compositions and methods useful for treating conditions associated with defects in cell proliferation, cell differentiation and/or cell survival. The invention is more particularly related to identifying protein tyrosine phosphatases (PTPs) that are reversibly modified, including PTPs that are reversibly oxidized components of inducible biological signaling pathways.

[0004] Reversible protein tyrosine phosphorylation, coordinated by the action of protein tyrosine kinases (PTKs) that phosphorylate certain tyrosine residues in polypeptides, and protein tyrosine phosphatases (PTPs) that dephosphorylate certain phosphotyrosine residues, is a key mechanism in regulating many cellular activities. It is becoming apparent that the diversity and complexity of the PTPs and PTKs are comparable, and that PTPs are equally important in delivering both positive and negative signals for proper function of cellular machinery. Regulated tyrosine phosphorylation contributes to specific pathways for biological signal transduction, including those associated with cell division, cell survival, apoptosis, proliferation and differentiation. Defects and/or malfunctions in these pathways may underlie certain disease conditions for which effective means for intervention remain elusive, including for example, malignancy, autoimmune disorders, diabetes, obesity and infection.

[0005] The protein tyrosine phosphatase (PTP) family of enzymes consists of more than 500 structurally diverse proteins that have in common the highly conserved 250 amino acid PTP catalytic domain, but which display considerable variation in their non-catalytic segments (Charbonneau and Tonks, 1992 Annu. Rev. Cell Biol. 8:463-493; Tonks, 1993 Semin. Cell Biol. 4:373-453). This structural diversity presumably reflects the diversity of physiological roles of individual PTP family members, which in certain cases have been demonstrated to have specific functions in growth, development and differentiation (Desai et al., 1996 Cell 84:599-609; Kishihara et al., 1993 Cell 74:143-156; Perkins et al., 1992 Cell 70:225-236; Pingel and Thomas, 1989 Cell 58:1055-1065; Schultz et al., 1993 Cell 73:1445-1454; Fukada et al., 1999 Growth Factors 17:81-91; Gutch et al., 1998 Genes Dev. 12:571-85; Marengere et al., 1996 Science 272:1170-73). PTPs participate in a variety of physiologic functions, providing a number of opportunities for therapeutic intervention in physiologic processes through alteration (i.e., a statistically significant increase or decrease) or modulation (e.g., up-regulation or down-regulation) of PTP activity. For example, therapeutic inhibition of PTPs such as PTP1B in the insulin signaling pathway may serve to augment insulin action, thereby ameliorating the state of insulin resistance common in Type II diabetes patients.

[0006] Although recent studies have also generated considerable information regarding the structure, expression and regulation of PTPs, the nature of many tyrosine phosphorylated substrates through which the PTPs exert their effects remains to be determined. Studies with a limited number of synthetic phosphopeptide substrates have demonstrated some differences in the substrate selectivities of different PTPs (Cho et al., 1993 Protein Sci. 2: 977-984; Dechert et al., 1995 Eur. J Biochem. 231:673-681). Analyses of PTP-mediated dephosphorylation of PTP substrates suggest that catalytic activity may be favored by the presence of certain amino acid residues at specific positions in the substrate polypeptide relative to the phosphorylated tyrosine residue (Salmeen et al., 2000 Molecular Cell 6:1401; Myers et al., 2001 J. Biol. Chem. 276:47771; Myers et al., 1997 Proc. Natl. Acad. Sci. USA 94:9052; Ruzzene et al., 1993 Eur. J Biochem. 211:289-295; Zhang et al., 1994 Biochemistry 33:2285-2290). Thus, although the physiological relevance of the substrates used in these studies is unclear, PTPs display a certain level of substrate selectivity in vitro.

[0007] The PTP family of enzymes contains a common evolutionarily conserved segment of approximately 250 amino acids known as the PTP catalytic domain. Within this conserved domain is a unique signature sequence motif,

[0008] [I/V]HCXAGXXR[S/T)G SEQ ID NO:98,

[0009] that is invariant among all PTPs. The cysteine residue in this motif is invariant in members of the family and is known to be essential for catalysis of the phosphotyrosine dephosphorylation reaction. It functions as a nucleophile to attack the phosphate moiety present on a phosphotyrosine residue of the incoming substrate. If the cysteine residue is altered by site-directed mutagenesis to serine (e.g., in cysteine-to-serine or “CS” mutants) or alanine (e.g., cysteine-to-alanine or “CA” mutants), the resulting PTP is catalytically deficient but retains the ability to complex with, or bind, its substrate, at least in vitro.

[0010] CS mutants of certain PTP family members, for example, MKP-1 (Sun et al., 1993 Cell 75:487), may effectively bind phosphotyrosyl polypeptide substrates in vitro to form stable enzyme-substrate complexes, thereby functioning as “substrate trapping” mutant PTPs. Such complexes can be isolated from cells in which both the mutant PTP and the phosphotyrosyl polypeptide substrates are present. According to non-limiting theory, expression of such a CS mutant PTP can thus antagonize the normal function of the corresponding wildtype PTP (and potentially other PTPs and/or other components of a PTP signaling pathway) via a mechanism whereby the CS mutant binds to and sequesters the substrate, precluding substrate interaction with catalytically active, wildtype enzyme (e.g., Sun et al., 1993).

[0011] CS mutants of certain other PTP family members, however, may bind phosphotyrosyl polypeptide substrates and form complexes that exist transiently and are not stable when the CS mutant is expressed in cells, i.e., in vivo. The CS mutant of PTP1B is an example of such a PTP. Catalytically deficient mutants of such enzymes that are capable of forming stable complexes with phophotyrosyl polypeptide substrates may be derived by mutating a wildtype protein tyrosine phosphatase catalytic domain invariant aspartate residue and replacing it with an amino acid that does not cause significant alteration of the Km of the enzyme but that results in a reduction in Kcat, as disclosed, for example, in U.S. Pat. Nos. 5,912,138 and 5,951,979, in U.S. application Ser. No. 09/323,426 and in PCT/US97/13016. For instance, mutation of Asp 181 in PTP1B to alanine to create the aspartate-to-alanine (D to A or DA) mutant PTP1B-D181A results in a PTP1B “substrate trapping” mutant enzyme that forms a stable complex with its phosphotyrosyl polypeptide substrate (e.g., Flint et al., 1997 Proc. Nat. Acad. Sci. USA 94:1680). Substrates of other PTPs can be identified using a similar substrate trapping approach, for example substrates of the PTP family members PTP-PEST (Garton et al., 1996 J. Mol. Cell. Biol. 16:6408), TCPTP (Tiganis et al., 1998 Mol. Cell Biol. 18:1622), PTP-HSCF (Spencer et al., 1997 J. Cell Biol. 138:845) and PTP-H1 (Zhang et al., 1999 J. Biol. Chem. 274:17806).

[0012] Mitogen-activated protein kinases (MAP-kinases) are present as components of conserved cellular signal transduction pathways that have a variety of conserved members. MAP-kinases are activated by phosphorylation at a dual phosphorylation motif with the sequence Thr-X-Tyr (by MAP-kinase kinases), in which phosphorylation at the tyrosine and threonine residues is required for activity. Activated MAP-kinases phosphorylate several transduction targets, including transcription factors. Inactivation of MAP-kinases is mediated by dephosphorylation at this site by dual-specificity phosphatases referred to as MAP-kinase phosphatases. In higher eukaryotes, the physiological role of MAP-kinase signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction via these pathways could lead to the development of treatments and preventive therapies for human diseases associated with MAP-kinase signaling, such as cancer.

[0013] Dual-specificity protein tyrosine phosphatases (dual-specificity phosphatases) are phosphatases that dephosphorylate both phosphotyrosine and phosphothreonine/serine residues (Walton et al., Ann. Rev. Biochem. 62:101-120, 1993). Several dual-specificity phosphatases that inactivate a MAP-kinase have been identified, including MKP-1 (WO 97/00315; Keyse and Emslie, Nature 59:644-647, 1992), MKP-2 (WO97/00315), MKP-4, MKP-5, MKP-7, Hb5 (WO 97/06245), PAC1 (Ward et al., Nature 367:651-654, 1994), HVH2 (Guan and Butch, J. Biol. Chem. 270:7197-7203, 1995) and PYST1 (Groom et al., EMBO J. 15:3621-3632, 1996). Expression of certain dual-specificity phosphatases is induced by stress or mitogens, but others appear to be expressed constitutively in specific cell types. The regulation of dual-specificity phosphatase expression and activity is critical for control of MAP-kinase mediated cellular functions, including cell proliferation, cell differentiation and cell survival. For example, dual-specificity phosphatases may function as negative regulators of cell proliferation. It is likely that there are many such dual-specificity phosphatases, with varying specificity with regard to cell type or activation. However, the regulation of dual specificity phosphatases remains poorly understood and only a relatively small number of dual-specificity phosphatases have been identified.

[0014] Currently, desirable goals for determining the molecular mechanisms that govern PTP-mediated cellular events include, inter alia, determination of PTP interacting molecules, substrates and binding partners, and identification of agents that regulate PTP activities. In some situations, however, current approaches may lead to an understanding of certain aspects of the regulation of tyrosine phosphorylation by PTPs, but still may not provide strategies to control specific tyrosine phosphorylation and/or dephosphorylation events within a cell. Accordingly, there is a need in the art for an improved ability to manipulate phosphotyrosine signaling, including intervention in the regulation of PTPs. An increased understanding of PTP regulation may facilitate the development of methods for modulating the activity of proteins involved in phosphotyrosine signaling pathways, and for treating conditions associated with such pathways.

[0015] Hence, and as also noted above, over the last fifteen years it has been established that the Protein Tyrosine Phosphatases (PTPs) are a large, structurally diverse family of receptor-like and non-transmembrane enzymes, which exhibit exquisite substrate specificity in vivo and are critical regulators of a wide array of cellular signaling pathways (Andersen et al., 2001 Mol. Cell. Biol. 21:7117; Tonks and Neel, 2001 Curr. Opin. Cell Biol. 13:182). An important area of investigation in the field remains the characterization of mechanisms by which the activity of the PTPs themselves may be regulated in vivo. Recently, the proposal that certain PTPs may be susceptible to oxidation and inactivation has introduced an additional tier of complexity to the regulation of this family of enzymes.

[0016] It is now apparent that reactive oxygen species (ROS) are not merely a harmful by-product of life in an aerobic environment. The importance of ROS in phagocytic cells, such as neutrophils, is well documented. Various stimuli lead to the assembly of a multi-component NADPH oxidase complex, which mediates a process known as the respiratory burst (DeLeo et al., 1996 J. Leukoc. Biol. 60:677). NADPH oxidase catalyses transfer of one electron from NADPH to molecular oxygen to generate superoxide anions, which in turn may yield hydrogen peroxide, either via protonation of superoxide or through the action of superoxide dismutase (Thelen et al., 1993 Physiol. Rev. 73:797). The large quantities of such ROS produced in phagocytic cells have been implicated as microbicidal agents and in certain pathological situations can result in host cell damage (Smith et al., 1991 Blood 77:673). However, many recent studies have revealed that the production of ROS is tightly regulated, engendering the concept that, at lower levels than those generated for a microbicidal function, ROS may also function in propagating a signaling response to extracellular stimuli (Finkel, 1998 Curr. Opin. Cell Biol. 10:248; Finkel, 2000 FEBS Lett. 476:52). Thus, in a manner analogous to reversible protein phosphorylation, the reversible oxidation of target proteins in a cell may regulate the function of those proteins in response to various agonists and thus elicit a cellular response to stimulation (Finkel, 1998).

[0017] Several lines of investigation have implicated ROS in the regulation of mitogenic signaling in mammalian cells (Adler et al., 1999 Oncogene 18:6104; Brummel et al., 1996 J. Biol. Chem. 271:1455-61; Chen et al., 1995 J. Biol. Chem. 270:28499; Sundaresan et al., 1995 Science 270:296). Mild oxidation can yield a stable sulfenic acid modification of cysteine residues (Cys-SOH) in selected proteins, including a variety of enzymes and transcription factors, which has the potential to regulate the function of those proteins (Claiborne et al., 1999 Biochemistry 38:15407). In order to understand the role of ROS and redox regulation in the control of signal transduction, it is particularly important to identify the targets of reversible oxidation in vivo. In this context, attention has been drawn to the PTPs, which together with the PTKs are responsible for maintaining a normal tyrosine phosphorylation status in vivo. As described above, the PTPs are characterized by a signature motif, I/V-H-C-X-X-G-X-X-R-S/T, which forms the base of the active site cleft and contains an invariant Cys residue (Barford et al., 1995 Nat. Struct. Biol. 2:1043). The catalytic mechanism involves a two-step process, commencing with nucleophilic attack by the Sγ atom of the catalytic Cys on the phosphorus atom of the phosphotyrosyl substrate, resulting in formation of a phospho-Cys intermediate. In the second step the transient phospho-enzyme intermediate is hydrolyzed by an activated water molecule (Barford et al., 1995). Due to the unusual environment of the PTP active site, the pKα of the sulfhydryl group of this Cys residue is extremely low (˜5.4 in PTP1B, (Lohse et al., 1997 Biochemistry 36:4568) and ˜4.7 in YOP, (Zhang et al., 1993 Biochemistry 32:9340)) compared to the typical pKα for Cys (˜8.5), which favors its function as a nucleophile but renders it susceptible to oxidation. It has now been shown in vitro that treatment with H₂O₂ of various PTPs (Lee et al., 1998 J. Biol. Chem. 273:15366), dual specificity phosphatses (Denu et al., 1998 Biochemistry 37:5633) and low molecular weight PTPs (Caselli et al., 1998 J. Biol. Chem. 273:32554) leads to oxidation of the active site Cys to sulfenic acid. Such oxidation results in inhibition of activity, because the modified Cys can no longer function as a phosphate acceptor in the first step of the PTP-catalyzed reaction.

[0018] Oxidation of Cys to sulfenic acid is reversible (Claiborne et al., 1999 Biochemistry 38:15407) and thus has the potential to form the basis of a mechanism for reversible regulation of PTP activity. In contrast, oxidation by the addition of 2 (sulfinic acid) or 3 (sulfonic acid) oxygens to the active site Cys is irreversible. Interestingly, glutathionylation of the sulfenic acid form of PTP1B has been reported (Barrett et al., 1999 Biochemistry 38:6699) and proposed as a mechanism to protect against further, irreversible oxidation and as an important step in the reverse, reduction mechanism. Stimulation of A431 cells with EGF was also shown to lead to the production of H₂O₂ and concomitant inhibition of PTP1B (Bae et al., 1997 J. Biol. Chem. 272:217). Increased production of intracellular oxidants may contribute to enhanced, tyrosine phosphorylation-dependent signaling, for example in response to growth factors (Bae et al., 1997; Bae et al., 2000 J. Biol. Chem. 275:10527; Sundaresan et al., 1995 Science 270:296), by transiently suppressing the enzymatic activity of members of the PTP family, thereby promoting a burst of PTK activity (Finkel, 1998; 2000).

[0019] However, it is unclear how broadly this phenomenon may apply across the PTP family, and methods have not previously been available for assessing potential reversible oxidation in a broad range of PTPs in a cellular context, i.e., within a living cell, or in vivo. In particular, there is a need for a method by which one or more oxidized/inactivated PTPs in a cell could be distinguished from reduced/activated PTPs in the cell, and in a manner which need not be specific for a particular PTP, or which need not require that each PTP being investigated be highly purified (e.g., specifically immunoprecipitated) or recombinantly cloned and expressed. An increased understanding of PTP regulation in biological signal transduction, including via inducible signaling pathways triggered by biological stimuli, may facilitate the development of methods for modulating the activity of proteins involved in PTK/PTP cascades, and for treating conditions associated with such cascades. The present invention fulfills these needs and further provides other related advantages.

SUMMARY OF THE INVENTION

[0020] It is an aspect of the present invention to provide a method for identifying a protein tyrosine phosphatase that is reversibly oxidized in a cell, comprising contacting a biological sample comprising a cell that comprises at least one protein tyrosine phosphatase with a stimulus under conditions and for a time sufficient to induce reversible oxidation of at least one protein tyrosine phosphatase in the cell; isolating anaerobically the protein tyrosine phosphatase in the presence of a sulthydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; determining under reducing conditions a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is reversibly oxidized in a cell. In one embodiment, the invention provides a method for identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is reversibly oxidized in a cell, comprising contacting a biological sample comprising a cell that comprises SHP-2 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of SHP-2 in the cell; isolating anaerobically SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; determining under reducing conditions a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, and wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is reversibly oxidized in a cell. In another embodiment, the invention provides a method for identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is reversibly oxidized in a cell, comprising contacting a biological sample comprising a cell that comprises PTP1B with a stimulus under conditions and for a time sufficient to induce reversible oxidation of PTP1B in the cell; isolating anaerobically PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and determining under reducing conditions a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is reversibly oxidized in a cell. In certain other embodiments of the present invention, a method is provided for identifying a TC45 protein tyrosine phosphatase (TC45) that is reversibly oxidized in a cell, comprising contacting a biological sample comprising a cell that comprises TC45 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of TC45 in the cell; isolating anaerobically TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; and determining under reducing conditions a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—-)080422, and wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is reversibly oxidized in a cell.

[0021] In certain embodiments the protein tyrosine phosphatase is PTP1B, PTP-PEST, PTPγ, LAR, MKP-1, CRYPα, PTPcryp2, DEP-1, SAP1, PCPTP1, PTPSL, STEP, HePTP, PTPIA2, PTPNP, PTPNE6, PTPμ, PTPX1, PTPX10, SHP-1, SHP-2, PTPBEM1, PTPBEM2, PTPBYP, PTPesp, PTPoc, PTP-PEZ, PTP-MEG1, MEG2, LC-PTP, TC-PTP, TC45, CD45, LAR, cdc14, RPTP-α, RPTP-ε, RKPTP, LyPTP, PEP, BDP1, PTP20, PTPK1, PTPS31, PTPGMC, GLEPP1, OSTPTP, PTPtep, PTPRL10, PTP2E, PTPD1, PTPD2, PTP36, PTPBAS, PTPBL, BTPBA14, PTPTyp, HDPTP, PTPTD14, PTPα, PTPβ, PTPδ, PTPε, PTPκ, PTPλ, PTPμ, PTPρ, PTPψ, PTPφ, PTPζ, PTPNU3 or PTPH1, or a PTP as presented in FIG. 8, or a dual specificity phosphatase including but not limited to PYST-1, MKP-1, MKP-2, MKP-4, MKP-5, MKP-7, hVH5, PAC1, VHR, or any dual specificity phosphatase disclosed in WO00/65069 (DSP-5), WO00/65068 (DSP-10), WO00/63393 (DSP-8), WO00/60100 (DSP-9), WO00/60099 (DSP-4), WO00/60098 (DSP-7), WO00/60092 (DSP-3), WO00/56899 (DSP-2), WO00/53636 (DSP-1), WO00/09656 (MKP), AU5475399 (MKP), AU8479498, WO99/02704, WO97/06245 (MKP), WO01/83723, WO01/57221, WO01/05983, WO01/02582, WO01/02581, U.S. application Ser. No. 09/955,732 (DSP-15), U.S. application Ser. No. 09/964,277 (DSP-16), U.S. A. No. 60/268,837 (DSP-17) or U.S. A. No. 60/291,476 (PTP). In certain embodiments the protein tyrosine phosphatase substrate comprises phosphorylated poly-(4:1)-Glu-Tyr, which in certain further embodiments comprises ³²P. In certain embodiments the detectably labeled protein tyrosine phosphatase substrate comprises a reporter molecule that is a fluorophore, a radionuclide, a chemiluminescent agent, an enzyme, an immunologically detectable epitope or a chromaphore. In certain further embodiments, the fluorophore is selected from fluorescein, rhodamine, Texas Red, AlexaFluor-594, AlexaFluor-488, Oregon Green, BODIPY-FL or Cy-5.

[0022] According to certain embodiments of the present invention, the protein tyrosine phosphatase substrate comprises a polypeptide sequence derived from a protein selected from a PDGF receptor, VCP, p130^(cas), EGF receptor, p210 bcr:abl, MAP kinase, She, insulin receptor, lck, T cell receptor zeta chain, lysozyme, or reduced and carboxyamidomethylated and maleylated lysozyme (RCML). In certain embodiments the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is an alkylating agent. In certain embodiments the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is iodoacetamide, iodoacetic acid, arsenic oxide, maleimide analog, haloacetimido analog, 4-vinylpyrimidine analog or N-ethylmaleimide. In certain embodiments the cell is a mammalian cell, which in certain embodiments is derived from a cell line and in certain further embodiments is derived from Rat-1 fibroblasts, COS cells, CHO cells or HEK-293 cells. In certain embodiments the step of isolating the protein tyrosine phosphatase comprises cell lysis, and in certain further embodiments the step of isolating comprises gel electrophoresis of the protein tyrosine phosphatase, and in certain further embodiments this step comprises electrophoresis of the protein tyrosine phosphatase in a gel comprising the detectably labeled protein tyrosine phosphatase substrate. In certain embodiments the method further comprises detecting the protein tyrosine phosphatase with an antibody that specifically binds to the phosphatase.

[0023] In certain embodiments of the present invention the stimulus increases reactive oxygen species in the sample, and in certain further embodiments the stimulus is a cytokine, a growth factor, a hormone, a cell stressor or a peptide. In certain embodiments the cell stressor is ROS or ultraviolet light. In certain embodiments the stimulus is PDGF, EGF, bFGF, insulin, GM-CSF, TGF-β1, IL-1, IL-3, IFN-γ, TNF-α, PHA, AT-2, thrombin, thyrotropin, parathyroid hormone, LPA, sphingosine-1-phosphate, serotonin, endothelin, acetylcholine, platelet activating factor, bradykinin or G-CSF.

[0024] In certain embodiments of the present invention there is provided a method for identifying a protein tyrosine phosphatase that is reversibly modified by a PTP active site-binding agent in a cell, comprising contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine with a biological sample comprising a cell that comprises at least one protein tyrosine phosphatase; isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine, a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is reversibly modified by a PTP active site-binding agent in a cell. In certain embodiments, the invention provides a method for identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is reversibly modified by a PTP active site-binding agent in a cell, comprising contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine with a biological sample comprising a cell that comprises SHP-2; isolating SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a SHP-2 active site invariant cysteine, a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, and wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is reversibly modified by a PTP active site-binding agent in a cell. In another embodiment, the invention provides a method for identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is reversibly modified by a PTP active site-binding agent in a cell, comprising contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine with a biological sample comprising a cell that comprises PTP1B; isolating PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a PTP1B active site invariant cysteine, a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is reversibly modified by a PTP active site-binding agent in a cell. In another embodiment, the invention provides a method for identifying a TC45 protein tyrosine phosphatase (TC45) that is reversibly modified by a PTP active site-binding agent in a cell, comprising contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine with a biological sample comprising a cell that comprises TC45; isolating TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a TC45 active site invariant cysteine, a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, and wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is reversibly modified by a PTP active site-binding agent in a cell.

[0025] In certain further embodiments, the step of isolating is performed anaerobically. In certain embodiments the PTP active site-binding agent is an agent that covalently binds to the PTP active site or an agent that non-covalently binds to the PTP active site. In certain embodiments the PTP active site-binding agent is a sulfonated compound or a vanadate compound. In certain embodiments the PTP active site-binding agent covalently and reversibly modifies a sulfhydryl group of a PTP active site invariant cysteine. In certain further embodiments the step of determining comprises reversing a covalent modification of a sulfhydryl group of a PTP active site invariant cysteine. In certain still further embodiments the step of reversing comprises contacting the PTP with a reducing agent. In certain still further embodiments the reducing agent is dithiothreitol, dithioerythritol or 2-mercaptoethanol. In certain embodiments the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is iodoacetamide, iodoacetic acid, arsenic oxide, maleimide analog, haloacetimido analog, 4-vinylpyrimidine analog or N-ethylmaleimide.

[0026] According to certain other embodiments of the present invention, there is provided a method for identifying a protein tyrosine phosphatase that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising contacting a biological sample comprising a cell that comprises at least one protein tyrosine phosphatase with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect protein tyrosine phosphatase active site invariant cysteine from modification; isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the protein tyrosine phosphatase active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is a reversibly modified component of an inducible biological signaling pathway in a cell. In a certain embodiment, the invention provides a method for identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising contacting a biological sample comprising a cell that comprises SHP-2 with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a SHP-2 active site invariant cysteine from modification; isolating the SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the SHP-2 active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, and wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is a reversibly modified component of an inducible biological signaling pathway in a cell. In another embodiment, that which is provided is a method for identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising contacting a biological sample comprising a cell that comprises PTP1B with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a PTP1B active site invariant cysteine from modification; isolating the PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the PTP1B active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is a reversibly modified component of an inducible biological signaling pathway in a cell. In a certain embodiment, the invention provides a method for identifying a TC45 protein tyrosine phosphatase (TC45) that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising contacting a biological sample comprising a cell that comprises TC45 with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a TC45 active site invariant cysteine from modification; isolating the TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the TC45 active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, and wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is a reversibly modified component of an inducible biological signaling pathway in a cell.

[0027] In certain embodiments the step of isolating is performed anaerobically. In certain embodiments the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is iodoacetamide, iodoacetic acid, arsenic oxide, maleimide analog, haloacetimido analog, 4-vinylpyrimidine analog or N-ethylmaleimide.

[0028] In certain other embodiments the invention provides a method for identifying an agent that alters an inducible biological signaling pathway, comprising (a) identifying a protein tyrosine phosphatase that is reversibly oxidized in a first biological sample comprising a cell that comprises at least one PTP according to the above described method steps of contacting, isolating and determining; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises the PTP that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of the PTP; (c) isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, and wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway. In certain embodiments the step of isolating in the method recited in (a) is performed anaerobically, and in certain embodiments the step of isolating recited in (c) is performed anaerobically.

[0029] In a certain embodiment, the invention provides a method for identifying an agent that alters an inducible biological signaling pathway, comprising (a) identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is reversibly oxidized in a cell according to a method comprising (i) contacting a first biological sample comprising a cell that comprises SHP-2 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of SHP-2 in the cell; (ii) isolating SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises SHP-2 that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of SHP-2; (c) isolating SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway.

[0030] In another embodiment of the invention is provided a method for identifying an agent that alters an inducible biological signaling pathway, comprising (a) identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is reversibly oxidized in a cell according to a method comprising (i) contacting a first biological sample comprising a cell that comprises PTP1B with a stimulus under conditions and for a time sufficient to induce reversible oxidation of PTP1B in the cell; (ii) isolating PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises PTP1B that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of PTP1B; (c) isolating PTP1B in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, and wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway.

[0031] The invention also provides a method for identifying an agent that alters an inducible biological signaling pathway, comprising (a) identifying a TC45 protein tyrosine phosphatase (TC45) that is reversibly oxidized in a cell according to a method comprising (i) contacting a first biological sample comprising a cell that comprises TC45 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of TC45 in the cell; (ii) isolating TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises TC45 that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of TC45; (c) isolating TC45 in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a TC45 active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, and wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway.

[0032] These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain aspects of this invention, and are therefore incorporated by reference in their entireties.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033]FIG. 1 shows a schematic for use of the “in-gel” phosphatase assay to identify PTPs that are susceptible to stimulus-induced oxidation.

[0034]FIG. 2 shows reversible oxidation of multiple PTPs concomitant with tyrosine phosphorylation in Rat-1 cells treated with H₂O₂. FIG. 2A illustrates an in-gel PTP assay. Serum-deprived Rat-1 cells were exposed to various concentrations of H₂O₂ for 1 min, harvested, and lysed in the absence (lane 1) or presence (lanes 2-7) of 10 mM iodoacetic acid (IAA). FIG. 2B presents an immunoblot of tyrosine phosphorylated proteins immunoprecipitated from lysates of H₂O₂-treated cells with Ab PT-66, then immunoblotted with anti-pTyr Ab (G104). FIG. 2C presents an in-gel PTP assay. After pre-incubation of Rat-1 cells in the absence or presence of 30 mM NAC, the cells were exposed to 200 μM H₂O₂ and lysed in the presence of 10 mM IAA at the indicated times. FIG. 2D shows an in-gel PTP assay of oxidized PTPs. Rat-1 cells were serum-starved in the absence or presence of 2.5 mM BSO for 16 h. H₂O₂ (200 μM) was added for 2 minutes, then removed by washing the cells with fresh culture media. Incubation was continued until the cells were harvested in lysis buffer containing 10 mM IAA at the times indicated. Arrows indicate PTPs for which reduction/reactivation displayed dependence on intracellular GSH.

[0035]FIG. 3 illustrates that H₂O₂-induced mitogenic signaling was associated with inactivation of PTPs. FIG. 3A presents an in-gel PTP assay. Purified SHP-2 (E76A mutant, 1 ng/lane) was incubated with PBS, H₂O₂, or t-BHP at 37° C. for 5 minutes. Aliquots were then incubated at room temperature for an additional 5 minutes, either in the absence (−IAA) or presence (+IAA) of 4 mM IAA. FIG. 3B shows images of ROS-induced DCF fluorescence in Rat-1 cells pre-loaded with 20 μM H₂DCFDA in the dark and then exposed to H₂O₂ or t-BHP (each at 200 EM). The cells are shown at magnification 400× (upper panels). Cells (1×10⁵) that underwent the same treatment as above were harvested and resuspended in Hanks' solution, then immediately subjected to flow cytometric analysis to measure ROS-induced DCF fluorescence (lower panels). The basal peak indicates background fluorescence, whereas the rightward shifted peak indicates ROS-induced DCF fluorescence. FIG. 3C depicts an in-gel PTP assay of oxidized PTPs. Cells were exposed to H₂O₂ and t-BHP (each at 200 μM) for the indicated times and lysed in the presence of 10 mM IAA. FIG. 3D presents an immunoblot of cell lysates prepared from cells exposed to H₂O₂ and t-BHP (each at 200 EM). Tyrosine phosphorylated proteins were immunoprecipitated with Ab PT-66, followed by immunoblotting with anti-pTyr Ab G104 (upper panel). An aliquot of lysate from each treatment was immunoblotted with anti-phospho-MAPK Ab and subsequently with anti-MAPK Ab (lower panel).

[0036]FIG. 4 shows PDGF induced oxidation of a 70 k PTP in Rat-1 cells. FIG. 4A represents an in-gel PTP assay. Serum-starved Rat-1 cells were exposed to 50 ng/ml PDGF-BB for the times indicated. Lysates were prepared in the presence of 10 mM IAA and subjected to in-gel PTP assay. The arrow indicates a 70 kDa PTP that was transiently oxidized following stimulation of Rat-1 cells with PDGF. The result shown is representative of four independent experiments. FIG. 4B: Cells were pre-incubated in the absence or presence of 30 mM NAC for 40 minutes. Excess NAC was removed prior to addition of PDGF (50 ng/ml). PDGF-induced oxidation of the 70 kDa PTP, which was impaired in the presence of NAC (arrow), was visualized by the modified in-gel PTP assay. FIG. 4C: Cells were treated with NAC and PDGF as described above. PDGFR was immunoprecipitated from lysates with Ab-X and immunoblotted with anti-pTyr Ab G104. The same filter was subsequently re-probed with Ab-X (upper panels). Aliquots of cell lysate from each treatment were immunoblotted with anti-phosho-MAPK Ab and re-probed with anti-MAPK Ab (lower panels).

[0037]FIG. 5 illustrates identification of the 70 kDa PTP that was susceptible to PDGF-induced oxidation as SHP-2. FIG. 5A: Serum-starved Rat-1 cells were exposed to PDGF (50 ng/ml) for the indicated times. The PDGFR and associated proteins were immunoprecipitated with antibody Ab-X, and pTyr proteins were visualized by immunoblotting with anti-pTyr Ab G104 (upper panel). The same filter was re-probed with anti-PDGFR, anti-SHP-2, anti-GAP, and anti-p85 PI3K Abs. The positions of PDGFR (solid arrow) and SHP-2 (open arrow) are indicated. FIG. 5B: Rat-1 cells, either untreated (−) or stimulated with 50 ng/ml PDGF (+), were harvested in lysis buffer containing 10 mM IAA. Lysates were incubated with antibody specific for either SHP-2 or SHP-1 and subjected to an in-gel PTP assay (upper panel). The arrow denotes the position of the 70 kDa PTP that was inactivated in response to PDGF and immunodepleted from cell lysates with antibodies to SHP-2. The lower panel illustrates an immunoblot to show the immunodepletion of SHP-2.

[0038]FIG. 6 demonstrates oxidation and inactivation of SHP-2 that was induced by PDGF but not by EGF or FGF. FIG. 6A: Rat-1 cells were incubated with 20 μM CM-H₂DCFDA in the dark for 20 minutes, then exposed to peptide growth factors (50 ng/ml) for an additional 10 mins. Images of ROS-induced DCF fluorescence are shown at 50× magnification. The data are representative of four independent experiments. FIG. 6B presents an in-gel PTP assay of oxidized PTPs. Cells were exposed to peptide growth factors for the indicated times and lysed in the presence of 10 mM IAA. FIG. 6C illustrates an immunoblot of cell lysates from each treatment group immunoblotted with anti-phosho-MAPK Ab (upper panel). The immunoblot was reprobed with anti-MAPK Ab (lower panel).

[0039]FIG. 7 shows that the pool of PDGFR-associated SHP-2, which was oxidized and inactivated in response to PDGF, was also involved in down-regulation of MAPK signaling. Rat-1 cells were transiently transfected with plasmids expressing WT or Y1009F mutant G-CSFR/PDGFR chimeric receptor, or with a plasmid encoding Green Fluorescence Protein (GFP) as a control for expression. FIG. 7A: After exposure to 100 ng/ml G-CSF for 5 min, the chimeric receptors were immunoprecipiated from lysates with antibody Ab-X and immunoblotted with anti-pTyr Ab G104. Immunoprecipitation of the receptors was verified by immunoblotting with Ab-X. The same filter was stripped and reprobed with anti-SHP-2 Ab. Expression of the chimeric receptors was verified by immunoblotting an aliquot of each lysate with Ab-X, which recognizes the intracellular segment of the PDGFR, and subsequently with anti-G-CSFR Ab, which recognizes the extracellular segment of chimeric receptors. FIG. 7B presents an in-gel PTP assay of Rat-1 cell lysates. Transfected Rat-1 cells were treated with G-CSF for the indicated times and then lysed in the presence of 10 mM IAA. The arrow denotes the position of SHP-2. FIG. 7C: The wild-type and mutant chimeric receptors were immunoprecipitated at the indicated times and immunoblotted with anti-pTyr Ab (G104) (top panel). The same filter was re-probed with anti-PDGFR Ab-X (bottom panel). FIG. 7D presents an immunoblot of cell lysates from each treatment blotted with anti-phosho-MAPK Ab (upper panel), and then re-probed with anti-MAPK Ab (lower panel). FIG. 7E presents a densitometric analysis of the gel image, which illustrates the ratio of phosphorylated MAPK (upper panel of 7D) over total MAPK (lower panel of 7D).

[0040]FIG. 8 presents a listing of PTPs.

[0041]FIG. 9 illustrates an in-gel PTP assay that shows protection from IAA-inactivation of PTP activity in PHA-stimulated peripheral blood mononuclear lymphocytes pre-treated with a PTP active site-binding agent.

[0042]FIG. 10 illustrates that hydrogen peroxide is a mediator of insulin signaling. FIG. 10A presents images of ROS-induced DCF fluorescence by fluorescence microscopy (50× magnification) of serum-starved Rat-1 cells exposed to 50 nM insulin. The data are representative of three independent experiments. FIG. 10B: Rat-1 cells were transiently transfected with different quantities of plasmid encoding human catalase. Two days after transfection, cells were serum-deprived and then stimulated with 50 nM insulin (INS) for 10 min. The cells were lysed, and catalase expression was verified by immunoblotting with anti-catalase antibody (top panel). The insulin receptor β (IR-β) subunit was immunoprecipitated from 400 μg of lysate with antibody 29B4. Immunoblotting was performed with anti-pYpY^(1162/1163) and subsequently with anti-IR-β antibody clone C-19 as a loading control (middle panel). An aliquot of lysate (30 μg) was subjected to immunoblotting with anti-phospho-PKB/AKT antibody. The same filter was then stripped and reprobed with anti-PKB/AKT antibody as a loading control (bottom panel).

[0043]FIG. 11 shows that insulin induced the transient oxidation of PTP1B and TC45. For each experiment, serum-starved Rat-1 cells were exposed to 50 nM insulin for the indicated times. Lysates were prepared under anaerobic conditions in the presence of 10 mM IAA and then subjected to in-gel PTP assays. FIG. 11A: The arrowheads indicate that 50 kDa and 45 kDa PTPs were transiently oxidized in response to insulin. Figure B and Figure C present in-gel PTP assays. Total lysate (400 μg) was immunoprecipitated with normal IgG (labeled C), anti-PTP1B antibody (FG6), or anti-TC45 antibody (191 OH) coupled to protein G-Sepharose beads. After immunoprecipitation, the immune complexes and supernatants were subjected to in-gel PTP assays. FIG. 11B shows immunodepletion of the 50 kDa PTP from the lysate with anti-PTP1B antibody. FIG. 11C illustrates immunodepletion of the 45 kDa PTP with antibody specific for TC45. The lane marked “Lys” represents cell lysate prior to immunodepletion. The lower panels illustrate immunoblots of total lysate and the supernatants following immunodepletion, using either anti-PTP1B antibody (FIG. 11B, lower panels) or anti-TC45 antibody (FIG. 11C, lower panels). The same blots were subsequently reprobed with anti-SHP-2 antibody to ensure loading of equal amounts of protein.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention is directed to a method of identifying any PTP that has been reversibly modified (e.g., oxidized, or reversibly modified by a PTP active site-binding agent) in a cellular context (i.e., within a cell, or in vivo), and in particular to any modification of a PTP active site invariant cysteine residue that can be reversed with a reducing agent. As described herein, typically such modification/oxidation of a PTP is accompanied by transient inactivation of the enzyme. Described herein is the unexpected discovery that reversible oxidation of a PTP in a cellular context renders such a PTP resistant to irreversible inactivation of the enzyme by a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a PTP active site invariant cysteine. This discovery is exploited to provide the invention method in a manner whereby one or more PTPs of interest may be non-specifically isolated from a cell—the invention method thus does not require any specific preparation and/or purification of a particular PTP that may be suspected of undergoing reversible modification/oxidation in vivo, such as recombinant cloning and expression of the PTP (which would require a polynucleotide encoding each PTP of interest) or immunoprecipitation of the PTP (which would require an antibody specific for each PTP of interest). Instead, the method may be practiced using a cell that comprises one or a plurality of PTPs, where the method permits determination of one or more reversibly modified/oxidized PTPs in a cell even where the identities of the particular PTPs that are expressed in the cell are not known a priori.

[0045] Accordingly, the one or more PTPs in a cell that are transiently modified/oxidized at the time the cell is contacted with the sulfhydryl-reactive agent that is capable of irreversibly (e.g., covalently) modifying a sulfhydryl group of a PTP active site invariant cysteine are not inactivated by the sulfhydryl-reactive agent, and such PTPs can subsequently be detected on the basis of their ability to catalytically dephosphorylate a PTP substrate after reversal (e.g., under reducing conditions) of the transient modification/oxidation event. Hence, and according to non-limiting theory, contact with a stimulus may induce a biological signaling pathway in a cell, which pathway comprises at least one PTP (and potentially a plurality of PTPs) that is reversibly modified at invariant cysteine (e.g., oxidized to form sulfenic acid) in response to the stimulus, and which is therefore reversibly protected from irreversible modification of its active site invariant cysteine during subsequent isolation of the PTP in the presence of a sulfhydryl-reactive agent (e.g., iodoacetamide) that is capable of so modifying the invariant cysteine. By way of contrast, any PTPs that are not reversibly and protectively modified in the course of the cellular response to the stimulus will be susceptible to permanent inactivation by the sulfhydryl agent during the PTP isolation procedure. Isolated PTPs are then exposed to conditions that reverse the reversible protection from modification of the PTP active site invariant cysteine (e.g., reducing conditions), such that PTP enzyme activity is restored only to those PTPs that have undergone the reversible protective modification. This activity can then be determined as a level of dephosphorylation of a detectably labeled PTP substrate as described herein. While this non-limiting theoretical model of the PTP modifications that may or may not occur in the course of practicing the subject invention method pertains to reversible oxidation of PTP active site invariant cysteine in response to a stimulus, as described herein the invention is not intended to be so limited, and also contemplates any other reversible modification to a PTP (e.g., by transient occupancy of the PTP active site by a PTP active site-binding agent that is capable of reversibly modifying a PTP active site invariant cysteine) that can be reversed, for example, a modification that is reversed by a reducing agent.

[0046] In certain embodiments the invention thus also provides a method for identifying a PTP that is a reversibly oxidized component of an inducible biological signaling pathway that is induced by a stimulus which may trigger reversible modification, for example, oxidation, of one or more PTPs. In such embodiments, any stimulus that is known to be, or suspected of being, capable of inducing a biological signaling pathway is contacted with a cell comprising one or a plurality of PTPs, and recoverable PTP catalytic activity is assessed following inactivation of unmodified (e.g., non-oxidized) PTPs with a sulfhydryl-reactive agent that is capable of irreversibly (e.g., covalently) modifying a sulfhydryl group of a PTP active site invariant cysteine. In certain related embodiments, prior to the step of contacting the cell with a stimulus, the cell may be contacted with a PTP active site-binding agent, to determine whether such a PTP active site-binding agent alters (i.e., increases or decreases in a statistically significant manner) the level of substrate dephosphorylation by one or more PTPs present in the cell, where PTPs that have retained the ability to dephosphorylate substrate have been reversibly and protectively modified (e.g., oxidized) as a result of the biological signaling pathway induced by the stimulus. Non-limiting examples of PTP active site-binding agents for use in such embodiments include PTP inhibitors as disclosed in Zhang et al. (2002 Ann. Rev. Pharmacol. Toxicol. 42:209-234), Iverson et al. (2001 Biochemistry 40:14812-20) and Jia et al. (2001 J. Med. Chem. 44:4584). Certain such agents may be sulfonated compounds or vanadate compounds (e.g., sodium orthovanadate); these and other PTP active site-binding agents are known to the art and/or may be identified according to established methodologies, including those described herein and in the cited references.

[0047] As described in greater detail below, in certain preferred embodiments determination of PTP substrate dephosphorylation, by one or more reversibly oxidized PTPs isolated anaerobically from a cell in the presence of a sulthydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a PTP active site invariant cysteine on any unmodified PTP, is accomplished using a modified “in-gel” PTP activity assay to allow visualization of a profile of PTPs that are reversibly oxidized following a particular stimulus. Anaerobic isolation conditions may be employed for one or more PTPs identified according to the present method, and whether and/or to what extent such conditions may be needed will vary with each PTP, as well as with the nature of the reversible modification (i.e., oxidative vs. non-oxidative) experienced by the PTP in a cell. Typically, anaerobic isolation of one or more PTPs relates to performing procedures for isolation of PTPs from a sample in an environment that is substantially reduced in its exposure to or content of oxygen gas, for instance, by conducting the isolation in an enclosure in which ambient air has been substantially replaced by an inert gas such as argon or nitrogen. Other procedures for creating an anaerobic atmosphere for PTP isolation may also be employed and will be familiar to those skilled in the art in view of the present disclosure, which describes examples of oxidative modification of PTPs that are detected following anaerobic isolation of the PTP.

[0048] Exemplary results using the modified “in-gel” PTP activity assay provided herein indicated that several PTPs could be identified that were oxidized and inactivated reversibly in Rat-1 cells following stimulation with H₂O₂, and that this event was important for peroxide-induced mitogenic signaling. Examples provided below show that platelet-derived growth factor (PDGF) stimulation of Rat-1 cells induced the oxidation and inhibition of the SH2 domain-containing PTP known as SHP-2 (see Hof et al., 1998 Cell 92:441-50), which facilitated mitogenic signaling in these cells in response to the growth factor. Additional examples provided show that insulin-induced signaling resulted in the oxidation and inhibition of two PTPs, PTP1B and the 45 kDa spliced variant of TC-PTP, TC45 (see Mosinger et al., 1992 Proc. Natl. Acad. Sci. USA 89:499-503; Tiganis et al., 1998 Mol. Cell Biol. 18:1622-34; Tiganis et al., 1999 J. Biol. Chem. 274:27768-75). The invention contemplates extending these analyses to identify and characterize other PTPs and their roles in the control of a broad array of biological signal transduction pathways.

[0049] Certain preferred embodiments of the invention therefore relate to a method wherein stimulus-induced oxidation within a cellular context (i.e., in vivo) provides a means of “tagging” (e.g., reversibly protecting from a sulfhydryl-reactive agent) those PTPs that are integral to the regulation of the cellular signal transduction pathways initiated by that stimulus. Alkylation with a sulfhydryl-reactive agent that is capable of covalently, and preferably irreversibly, modifying a sulfhydryl group of a PTP active site invariant cysteine, for example, iodoacetamide (IAA), can be used to inactivate and thereby functionally subtract out the bulk of the PTPs, which being unaffected by the stimulus and hence not transiently oxidized, are unprotected from the sulfhydryl reagent. Following reduction to reverse the transient oxidation and return the transiently inactivated PTP to an active state, the stimulus-responsive (i.e., oxidatively protected) PTPs can be isolated and identified on the basis of phosphatase activity, demonstrable as dephosphorylation of a PTP substrate using any of a variety of well established procedures as provided herein and as known to the art. (See, e.g., Flint et al., 1993 EMBO J. 12:1937-1946; Tonks et al., 1991 Meths. Enzymol. 201:427-42; Tonks et al., 1988 J. Biol. Chem. 263:6722). Reducing conditions that are suitable for determining PTP substrate dephosphorylation by a catalytically competent phosphatase (i.e., an “active” PTP) can be achieved using compositions and methods well known to the art in view of the present disclosure. The precise reducing conditions may vary as a function of the particular PTP for which activity following reversible inactivation is to be determined; common reducing agents for establishing such conditions include, by way of illustration and not limitation, dithiothreitol (Cleland's reagent), dithioerythritol and 2-mercaptoethanol (β-mercaptoethanol).

[0050] The “in-gel” phosphatase assay described herein comprises a modification of an existing technique (Burridge and Nelson, 1995 Anal. Biochem. 232, 56-64) and provides one such preferred procedure for demonstrating PTP activity toward (phosphorylated) PTP substrates as provided herein. The modified in-gel phosphatase assay features electrophoretic separation and renaturation, under reducing conditions, of a plurality of PTPs in a gel impregnated with a detectably labeled PTP substrate, but with regard to the step of determining dephosphorylation of a detectably labeled PTP substrate by a PTP according to the methods of disclosed herein, the invention is not intended to be so limited. For example some PTPs, in particular certain of the receptor-like forms, may not renature efficiently in the “in-gel” PTP activity assay (Burridge and Nelson, 1995). The invention therefore contemplates incorporation of any suitable method for determining a level of dephosphorylation of a detectably labeled PTP substrate by a PTP, which may vary according to the physicochemical properties (e.g., conformational stability in a variety of chemical environments) of particular PTPs, and which can be selected by a person having ordinary skill in the art readily and without undue experimentation based on the instant disclosure.

[0051] For example, suitable phosphatase assays may include in-gel assays using non-denaturing gel systems. Additional methodologies for assaying PTP-mediated substrate dephosphorylation may include proteomics-based strategies, for example, using solid-phase immobilized, broad specificity PTP active site-directed inhibitors (such as phenylarsine oxide coupled to agarose) as affinity matrices for the purification and identification of oxidation-sensitive PTPs. As also noted above, other embodiments contemplate exposure of cells comprising an inducible biological signaling pathway to one or more PTP active site-binding agents (e.g., Zhang et al. 2002 Ann. Rev. Pharmacol. Toxicol. 42:209-234; Iverson et al. 2001 Biochemistry 40:14812-20; Jia et al. 2001 J. Med. Chem. 44:4584) prior to contacting these cells with a stimulus that induces the signaling pathway. Recoverable activity may then be assayed in PTPs that are protectively modified, by reversible oxidation, when the PTPs are isolated in the presence of a sulfhydryl-reactive agent, wherein further the active site-binding agent may be employed to facilitate PTP isolation. By combining these approaches with the use of substrate-trapping mutant forms of the PTPs thus identified (e.g., Flint et al., 1997 Proc. Natl. Acad. Sci. USA 94:1680-1685), the physiological substrate specificities of these enzymes can be determined to further characterize the components of biological signaling pathways that comprise PTPs. Additional characterization of biological signaling pathway components identified using the methods of the present invention may be achieved using specific binding proteins to detect such components. Preferred examples of such binding proteins include antibodies, receptors, counterreceptors, ligands, and the like, for example, an antibody that, as provided herein, specifically binds to a phosphatase, or an antibody that specifically binds to a phosphopeptide such as phosphotyrosine, phosphoserine or phosphothreonine.

[0052] PTPs

[0053] As used herein, a phosphatase is a member of the PTP family if it contains the signature motif [I/V]HCXAGXXR[S/T]G (SEQ ID NO:98). Dual specificity PTPs, i.e., PTPs which dephosphorylate both phosphorylated tyrosine and phosphorylated serine or threonine, are also suitable for use in the invention. Appropriate PTPs for use in the present invention include any PTP family member, for example, any PTP described in Andersen et al. (2001 Mol. Cell. Biol. 21:7117) or shown in FIG. 8, or any dual specificity phosphatase including but not limited to PYST-1, MKP-1, MKP-2, MKP-4, MKP-5, MKP-7, hVH5, PAC1, VHR, or any dual specificity phosphatase disclosed in WO0/65069 (DSP-5), WO00/65068 (DSP-10), WO00/63393 (DSP-8), WO00/60100 (DSP-9), WO00/60099 (DSP-4), WO00/60098 (DSP-7), WO00/60092 (DSP-3), WO00/56899 (DSP-2), WO00/53636 (DSP-1), WO00/09656 (MKP), AU5475399 (MKP), AU8479498, WO99/02704, WO97/06245 (MKP), WO01/83723, WO01/57221, WO01/05983, WO01/02582, WO01/02581, U.S. application Ser. No. 09/955,732 (DSP-15), U.S. application Ser. No. 09/964,277 (DSP-16), U.S. A. No. 60/268,837 (DSP-17) or U.S. A. No. 60/291,476 (PTP) and in certain preferred embodiments including, but not limited to, PTP1B (e.g., GenBank Accession Nos. M31724 (SEQ ID NOS: 1-2); NM_(—)002827 (SEQ ID NOS: 3-4); NM_(—)011201 (SEQ ID NOS: 5-6); M31724 (SEQ ID NOS: 7-8); M33689 (SEQ ID NOS: 9-10); M33962 (SEQ ID NOS: 11-12)), PTP-PEST (e.g., GenBank Accession Nos. D13380 (SEQ ID NOS: 68-69); M93425 (SEQ ID NOS: 70-71); S69184 (SEQ ID NOS: 72-73); X86781 (SEQ ID NOS: 74-75); D38072 (SEQ ID NOS: 76-77)), PTPγ, LAR, MKP-1, CRYPα, PTPcryp2, DEP-1 (e.g., GenBank Accession Nos. U10886 (SEQ ID NOS: 41-42); D37781 (SEQ ID NOS: 43-44); AAB26475 (SEQ ID NO: 45); D45212 (SEQ ID NOS: 46-47); U40790 (SEQ ID NOS: 48-49)), SAP1, PCPTP1, PTPSL, STEP, HePTP, PTPIA2, PTPNP, PTPNE6, PTPμ, PTPX1, PTPX10, SHP-1 (e.g., GenBank Accession Nos. M74903 (SEQ ID NOS: 86-87); X62055 (SEQ ID NOS: 88-89); M77273 (SEQ ID NOS: 90-91); X82817 (SEQ ID NO: 92); X82818 (SEQ ID NO: 93); M90388 (SEQ ID NOS: 94-95); U77038 (SEQ ID NOS: 96-97)), SHP-2 (e.g., GenBank Accession Nos. D13540 (SEQ ID NOS: 25-26); L03535 (SEQ ID NOS: 27-28); L07527 (SEQ ID NOS: 29-30); X70766 (SEQ ID NOS: 31-32); L08807 (SEQ ID NO: 33); S78088 (SEQ ID NOS: 34-35); S39383 (SEQ ID NO: 36); D84372 (SEQ ID NOS: 13-14); U09307 (SEQ ID NOS: 15-16)), PTPBEM1, PTPBEM2, PTPBYP, PTPesp, PTPoc, PTP-PEZ, PTP-MEG1, MEG2, LC-PTP, TC-PTP (e.g., GenBank Accession Nos. M25393 (SEQ ID NOS: 17-18); M81478 (SEQ ID NO: 19); M80737 (SEQ ID NO: 20); M81477 (SEQ ID NOS: 21-22); X58828 (SEQ ID NOS: 23-24); NM_(—)002828 (SEQ ID NOS: ______ and ______), TC45 (e.g., NM_(—)080422 (SEQ ID NOS: ______ and ______), CD45 (e.g., GenBank Accession Nos. Y00638 (SEQ ID NOS: 78-79); Y00062 (SEQ ID NOS: 80-81); M92933 (SEQ ID NOS: 82-83); M10072 (SEQ ID NOS: 84-85); LAR, cdc14 (which includes cdc14a (e.g., GenBank Accession Nos. AF122013 (SEQ ID NOS: 50-51); AF064102 (SEQ ID NOS: 52-53); AF064103 (SEQ ID NOS: 54-55); Li et al., 1997 J. Biol. Chem. 272:29403; U.S. Pat. No. 6,331,614) and cdc14b (e.g., GenBank Accession Nos. AF064104 (SEQ ID NOS: 56-57); AF064105 (SEQ ID NOS: 58-59); AF023158 (SEQ ID NOS: 60-61); Li et al., 1997 J Biol. Chem. 272:29403), RPTP-α, RPTP-ε, RKPTP, LyPTP, PEP, BDP1, PTP20, PTPK1, PTPS31, PTPGMC, GLEPP1, OSTPTP, PTPtep, PTPRL10, PTP2E, PTPD1, PTPD2, PTP36, PTPBAS, PTPBL, BTPBA14, PTPTyp, HDPTP, PTPTD14, PTPα, PTPβ, PTPδ, PTPε (e.g., GenBank Accession Nos. X54134 (SEQ ID NOS: 62-63); D83484 (SEQ ID NOS: 64-65); D78610 (SEQ ID NOS: 66-67)), PTPκ, PTPλ, PTPμ, PTPρ, PTPψ, PTPφ, PTPζ, PTPNU3 and PTPH1 (e.g., GenBank Accesion Nos. M64572 (SEQ ID NOS: 37-38) and S39392 (SEQ ID NOS: 39-40)), and mutated forms thereof.

[0054] As noted above, and particularly with regard to the identification and selection of suitable PTP substrates as provided herein, including peptide fragments having sequences derived from portions of polypeptides identified as physiological PTP substrates, the present invention relates in part to the use of substrate trapping mutant protein tyrosine phosphatases (PTPs) derived from a PTP that has been mutated in a manner that does not cause significant alteration of the Michaelis-Menten constant (Km) of the enzyme, but which results in a reduction of the catalytic rate constant (Kcat). In certain embodiments, the PTP catalytic domain invariant aspartate residue may be replaced with another amino acid. In certain other embodiments, the substrate trapping mutant PTP may be mutated by replacement of a catalytic domain cysteine residue. Under certain conditions in vivo, a PTP enzyme may itself undergo tyrosine phosphorylation in a manner that can alter interactions between the PTP and other molecules, including PTP substrates. Thus, in certain embodiments the substrate trapping mutant PTP may be further mutated by replacement of at least one tyrosine residue with an amino acid that is not capable of being phosphorylated. Substrate trapping mutant PTPs are disclosed, for example, in U.S. Pat. Nos. 5,912,138 and 5,951,979 and in U.S. application Ser. No. 09/334,575. Disclosure relating to the preparation and use of substrate trapping mutant PTPs, including PTPs having at least one tyrosine residue replaced with an amino acid that is not capable of being phosphorylated, and including identification of physiological PTP substrates, can be found in WO 00/75339.

[0055] According to particularly preferred embodiments of the methods of the present invention, PTPs in which the wildtype catalytic domain invariant cysteine residues are present, may be inactivated by sulfhydryl-reactive agents according to assay methods as disclosed herein. Preferably, such agents are sulfhydryl-reactive agents that are capable of covalently and irreversibly modifying a sulthydryl group of a PTP active site invariant cysteine, for example alkylating agents such as N-ethylmaleimide (NEM), iodoacetamide (IAA) or iodoacetic acid. Other sulfhydryl-reactive agents that are capable of covalently modifying a sulfhydryl group of a PTP active site invariant cysteine include arsenic oxide; 4-vinyl pyridine and analogs and derivatives thereof; maleimide analogs conforming to the following structural formula:

[0056] wherein X is the remainder of the molecule, including linkers;

[0057] or halo-acetamido analogs conforming to the following structural formula:

[0058] wherein X is the remainder of the molecule, including linkers.

[0059] Useful sulthydryl-reactive agents may also include other cysteine-reactive compounds, i.e., chemically reactive species that covalently modify cysteine and/or adjacent residues, further including such compounds which do so stoichiometrically and without selectivity for PTP proteins or polypeptides.

[0060] The term “isolated” means that the material is removed from its original environment (e.g., the natural environment if it is naturally occurring). For example, a naturally occurring nucleic acid or polypeptide present in a living animal is not isolated, but the same nucleic acid or polypeptide, separated from some or all of the co-existing materials in the natural system, is isolated. Such nucleic acid could be part of a vector and/or such nucleic acid or polypeptide could be part of a composition (e.g., a cell lysate), and still be isolated in that such vector or composition is not part of the natural environment for the nucleic acid or polypeptide. The term “gene” means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region “leader and trailer” as well as intervening sequences (introns) between individual coding segments (exons).

[0061] Samples

[0062] According to the present invention, there is provided a method of identifying a protein tyrosine phosphatase that has been reversibly oxidized, typically in a biological sample. A “sample” as used herein refers to a biological sample containing at least one protein tyrosine phosphatase, and may be provided by obtaining a blood sample, biopsy specimen, tissue explant, organ culture or any other tissue or cell preparation from a subject or a biological source. A sample may further refer to a tissue or cell preparation in which the morphological integrity or physical state has been disrupted, for example, by dissection, dissociation, solubilization, fractionation, homogenization, biochemical or chemical extraction, pulverization, lyophilization, sonication or any other means for processing a sample derived from a subject or biological source. In certain preferred embodiments, the sample is a cell that comprises at least one PTP, and in certain particularly preferred embodiments the cell comprises an inducible biological signaling pathway, at least one component of which is a PTP. In particularly preferred embodiments the cell is a mammalian cell, for example, Rat-1 fibroblasts, COS cells, CHO cells, HEK-293 cells or other well known model cell lines, which are available from the American Type Culture Collection (ATCC, Manassas, Va.).

[0063] The subject or biological source may be a human or non-human animal, a primary cell culture or culture adapted cell line including but not limited to genetically engineered cell lines that may contain chromosomally integrated or episomal recombinant nucleic acid sequences, immortalized or immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiatable cell lines, transformed cell lines and the like. Optionally, in certain situations it may be desirable to treat cells in a biological sample with hydrogen peroxide and/or with another agent that directly or indirectly promotes reactive oxygen species (ROS) generation, including biological stimuli as described herein; in certain other situations it may be desirable to treat cells in a biological sample with a ROS scavenger, such as N-acetyl cysteine (NAC) or superoxide dismutase (SOD) or other ROS scavengers known in the art; in other situations cellular glutathione (GSH) may be depleted by treating cells with L-buthionine-SR-sulfoximine (Bso); and in other circumstances cells may be treated with pervanadate to enrich the sample in tyrosine phosphorylated proteins. Other means may also be employed to effect an increase in the population of tyrosine phosphorylated proteins present in the sample, including the use of a subject or biological source that is a cell line that has been transfected with at least one gene encoding a protein tyrosine kinase.

[0064] Additionally or alternatively, a biological signaling pathway may be induced in subject or biological source cells by contacting such cells with an appropriate stimulus, which may vary depending upon the signaling pathway under investigation, whether known or unknown. For example, a signaling pathway that, when induced, results in protein tyrosine phosphorylation and/or protein tyrosine dephosphorylation may be stimulated in subject or biological source cells using any one or more of a variety of well known methods and compositions known in the art to stimulate protein tyrosine kinase and/or PTP activity. These stimuli may include, without limitation, exposure of cells to cytokines, growth factors, hormones, peptides, small molecule mediators, cell stressors (e.g., ultraviolet light; temperature shifts; osmotic shock; ROS or a source thereof, such as hydrogen peroxide, superoxide, ozone, etc. or any agent that induces or promotes ROS production (see, e.g., Halliwell and Gutteridge, Free Radicals in Biology and Medicine (3^(rd) Ed.) 1999 Oxford University Press, Oxford, UK); heavy metals; alcohol) or other agents that induce PTK-mediated protein tyrosine phosphorylation and/or PTP-mediated phosphoprotein tyrosine dephosphorylation. Such agents may include, for example, interleukins (e.g., IL-1, IL-3), interferons (e.g., IFN-γ), human growth hormone, insulin, epidermal growth factor (EGF), platelet derived growth factor (PDGF), granulocyte colony stimulating factor (G-CSF), granulocyte-megakaryocyte colony stimulating factor (GM-CSF), transforming growth factor (e.g., TGF-β1), tumor necrosis factor (e.g., TNF-α) and fibroblast growth factor (FGF; e.g., basic FGF (bFGF)), any agent or combination of agents capable of triggering T lymphocyte activation via the T cell receptor for antigen (TCR; TCR-inducing agents may include superantigens, specifically recognized antigens and/or MHC-derived peptides, MHC peptide tetramers (e.g., Altman et al., 1996 Science 274:94-96) TCR-specific antibodies or fragments or derivatives thereof), lectins (e.g., PHA, PWM, ConA, etc.), mitogens, G-protein coupled receptor agonists such as angiotensin-2, thrombin, thyrotropin, parathyroid hormone, lysophosphatidic acid (LPA), sphingosine-1-phosphate, serotonin, endothelin, acetylcholine, platelet activating factor (PAF) or bradykinin, as well as other agents with which those having ordinary skill in the art will be familiar (see, e.g., Rhee et al., Oct. 10, 2000 Science's stke, <http:www.stke.org/cgl/content/full/OC_sigtrans;2000/53/pel, and references cited therein; see also Gross et al., 1999 J. Biol. Chem. 274:26378-86; Prenzel et al., 1999 Nature 402:884-88; Ushio-Fukai et al., 1999 J. Biol. Chem. 274:22699-704; Holland et al., 1998 Endothelium 6:113-21; Daub et al., 1997 EMBO J. 16:7032-44; Krypianou et al., 1997 Prostate 32:266-71; Marumo et al., 1997 Circulation 96:2361-67).

[0065] As noted above, regulated tyrosine phosphorylation contributes to specific pathways for biological signal transduction, including those associated with cell division, cell survival, apoptosis, proliferation and differentiation, and “inducible signaling pathways” in the context of the present invention include transient or stable associations or interactions among molecular components involved in the control of these and similar processes in cells. Depending on the particular pathway of interest, an appropriate parameter for determining induction of such pathway may be selected. For example, for signaling pathways associated with cell proliferation, there is available a variety of well known methodologies for quantifying proliferation, including, for example, incorporation of tritiated thymidine into cellular DNA, monitoring of detectable (e.g. fluorimetric or calorimetric) indicators of cellular respiratory activity, or cell counting, or the like. Similarly, in the cell biology arts there are known multiple techniques for assessing cell survival (e.g., vital dyes, metabolic indicators, etc.) and for determining apoptosis (e.g., annexin V binding, DNA fragmentation assays, caspase activation, etc.). Other signaling pathways will be associated with particular cellular phenotypes, for example specific induction of gene expression (e.g., detectable as transcription or translation products, or by bioassays of such products, or as nuclear localization of cytoplasmic factors), altered (e.g., statistically significant increases or decreases) levels of intracellular mediators (e.g., activated kinases or phosphatases, altered levels of cyclic nucleotides or of physiologically active ionic species, etc.), or altered cellular morphology, and the like, such that cellular responsiveness to a particular stimulus as provided herein can be readily identified to determine whether a particular cell comprises an inducible signaling pathway.

[0066] For example, a biological signaling pathway may be induced in a cell by a stimulus that induces or promotes ROS production. Cells may be stimulated with any one or more of a number of stimuli as provided herein, including those provided above, such as a cytokine, a growth factor (e.g., PDGF), a hormone such as a polypeptide hormone (e.g., insulin), a cell stressor, or a peptide. Intracellular production of ROS, including hydrogen peroxide, may be determined according to established methodologies using direct or indirect ROS indicators, for example, by using fluorescent ROS indicators such as 2′,7′-dichlorofluorescein diacetate (H₂DCFDA) or 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H₂DCFDA). ROS-induced DCF fluorescence can then be measured, for instance, by fluorimetry, fluorescence microscopy or flow cytofluorimetry, or according to other methods known in the art. ROS may also be detected in biological systems by any of a variety of other techniques, including spin trapping, in which a reactive radical is allowed to react with a molecular trap to produce a long-lived radical, and also including molecular fingerprinting, which measures end-products of oxidative damage. Specific compositions and methods for such trapping, as well as other means for determining ROS, are known to the art and selection of a technique for identifying ROS may depend upon the particular reactive oxygen species that is to be detected (see, e.g., Halliwell and Gutteridge, supra).

[0067] The effect of ROS production on phosphorylation and/or dephosphorylation of one or more polypeptide components of a signaling pathway may be examined by determining the level of phosphorylation of components in the particular pathway. For example, treatment of Rat-1 cells with PDGF, which has been shown to induce ROS production in various cell types (Bae et al., 2000, supra; Sundaresan et al. supra), results in a rapid increase in the tyrosine phosphorylation of cellular proteins and enhanced phosphorylation of MAPKs (see also Bazenet et al., 1996 Mol. Cell Biol. 16:6926-36; Klinghoffer et al., 2001 Mol. Cell 78:343-54; Yu et al., 2000 J. Biol. Chem. 275:19076-82). As another example, the effect of ROS production in the signal transduction pathway induced by insulin may be evaluated by determining the level of tyrosine phosphorylation of insulin receptor beta (IR-β) and/or of the downstream signaling molecule PKB/Akt and/or of any other downstream polypeptide that may be a component of a particular signal transduction pathway as provided herein.

[0068] A number of methods are described herein and known in the art for detection of one or more particular signal transduction pathway component polypeptides, and for determination of whether such polypeptides may be tyrosine-phosphorylated in cells following stimulation as described herein. Also described herein are methods for detecting such polypeptides, including determination of altered (i.e., increased or decreased with statistical significance) tyrosine phosphorylation that may further include determination of the phosphorylation state of particular tyrosine residues at specified positions within a polypeptide sequence, which altered tyrosine phosphorylation may in certain embodiments be accompanied by the presence or absence of ROS production in the cells from which such polypeptides are obtained (e.g., as a result of exposure to a stimulus). Non-limiting examples of such detection methods include the use of reagents that specifically bind to signaling pathway components, for example, by immunological methods (e.g. immunoprecipitation, immunoblotting, ELISA, radioimmunoprecipitation, and the like) that employ antibodies as provided herein that are capable of specifically binding a particular signaling pathway component polypeptide or a particular tyrosine-phosphorylated polypeptide. Additionally and as described in greater detail herein, in certain embodiments cellular ROS production induced by a stimulus may be partially or completely impaired, abrogated, inhibited or otherwise counteracted by inclusion of a ROS-neutralizing agent, for instance, by the presence of enzymes such as catalase (H₂O₂:H₂O₂ oxidoreductase) or superoxide dismutase (SOD; superoxide:superoxide oxidoreductase), or of free-radical scavengers or other agents known to the art that are capable of neutralizing the effects of ROS (see, e.g., Halliwell and Gutteridge, supra).

[0069] Substrates

[0070] In preferred embodiments, a PTP substrate may be any naturally or non-naturally occurring phosphorylated peptide, polypeptide or protein that can specifically bind to and/or be dephosphorylated by a PTP (including dual specificity phosphatases) as provided herein, or any other phosphorylated molecule that can be a substrate of a PTP family member as provided herein. Non-limiting examples of known PTP substrates include the proteins VCP (see, e.g., Zhang et al., 1999 J. Biol. Chem. 274:17806, and references cited therein), p130^(cas), EGF receptor, p210 bcr:abl, MAP kinase, Shc (Tiganis et al., 1998 Mol. Cell. Biol. 18:1622-1634), insulin receptor, lck (lymphocyte specific protein tyrosine kinase, Marth et al., 1985 Cell 43:393), T cell receptor zeta chain, and phosphatidylinositol 3,4,5-triphosphate (Maehama et al., 1998 J. Biol. Chem. 273:13375).

[0071] As another example, tyrosine phosphorylated peptides identified with mutant PTPs from peptide libraries by the methods of Songyang et al. (1995 Nature 373:536-539; 1993 Cell 72:767-778) can be used herein in place of the complete tyrosine phosphorylated protein in PTP binding and/or catalytic assays. Optionally, candidate peptide sequences may be selected and optimized for dephosphorylation or binding activity as described herein using other techniques such as affinity selection followed by mass spectrometric detection (e.g., Pellegrini et al., 1998 Biochemistry 37:15598; Huyer et al., 1998 Anal. Biochem. 258:19) or by “inverse alanine scanning” (e.g., Vetter et al., 2000 J. Biol. Chem. 275:2265). In certain particularly preferred embodiments, a PTP substrate is a tyrosine phosphorylated peptide, which may include a partial amino acid sequence, portion, region, fragment, variant, derivative or the like from a naturally or non-naturally tyrosine-phosphorylated peptide, polypeptide or protein that can specifically bind to and/or be dephosphorylated by a PTP. In preferred embodiments, the PTP substrate is detectably labeled as provided herein, such that it can be detectably dephosphorylated by a PTP family member, as also provided herein. A PTP substrate that is a tyrosine phosphorylated peptide typically comprises 2-700 amino acids. Preferred substrates as described herein include a random amino acid copolymer of poly-Glu-Tyr wherein the Glu:Tyr ratio is approximately 4:1; preparations of this copolymer may be polydisperse with respect to molecular mass and in certain preferred embodiments may have an average molecular mass of approximately 55-65 kDa. Other preferred substrates include reduced and carboxyamidomethylated and maleylated lysozyme (RCML, Flint et al., 1993 EMBO J. 12:1937-1946). In certain other embodiments, a PTP substrate may comprise a phosphotyrosine residue having an attached fluorescent label.

[0072] Identification and selection of PTP substrates as provided herein, for use in the present invention, may be performed according to procedures with which those having ordinary skill in the art will be familiar, or may, for example, be conducted according to the disclosures of WO 00/75339 or U.S. application Ser. No. 09/334,575 and references cited therein. The phosphorylated protein/PTP complex may be isolated, for example, by conventional isolation techniques as described in U.S. Pat. No. 5,352,660, including salting out, chromatography, electrophoresis, gel filtration, fractionation, absorption, polyacrylamide gel electrophoresis, agglutination, combinations thereof or other strategies. PTP substrates that are known may also be prepared according to well known procedures that employ principles of molecular biology and/or peptide synthesis (e.g., Ausubel et al., 1993 Current Protocols in Molecular Biology, Greene Publ. Assoc. Inc. & John Wiley & Sons, Inc., Boston, Mass.; Sambrook et al., 1989 Molecular Cloning, Second Ed., Cold Spring Harbor Laboratory, Plainview, N.Y.; Fox, 1995 Molec. Biotechnol. 3:249; Maeji et al., 1995 Pept. Res. 8:33).

[0073] The PTP substrate peptides of the present invention may therefore be derived from PTP substrate proteins, polypeptides and peptides as provided herein having amino acid sequences that are identical or similar to tyrosine phosphorylated PTP substrate sequences known in the art. For example by way of illustration and not limitation, peptide sequences derived from the known PTP substrate proteins referred to above are contemplated for use according to the instant invention, as are peptides having at least 70% similarity (preferably 70% identity), more preferably 90% similarity (more preferably 90% identity) and still more preferably 95% similarity (still more preferably 95% identity) to the polypeptides described in references cited herein and in the Examples and to portions of such polypeptides as disclosed herein. As known in the art “similarity” between two polypeptides is determined by comparing the amino acid sequence and conserved amino acid substitutes thereto of the polypeptide to the sequence of a second polypeptide (e.g., using GENEWORKS, Align or the BLAST algorithm, or another algorithm, as described above).

[0074] Thus, according to the present invention, substrates may include full length tyrosine phosphorylated proteins and polypeptides as well as fragments (e.g., portions), derivatives or analogs thereof that can be phosphorylated at a tyrosine residue. Such fragments, derivatives and analogs include any PTP substrate polypeptide that retains at least the biological function of interacting with a PTP as provided herein, for example by forming a complex with a PTP and/or, in certain embodiments, undergoing PTP-catalyzed dephosphorylation. A fragment, derivative or analog of a peptide, protein or polypeptide as provided herein, including a PTP substrate polypeptide, and further including PTP substrates that are fusion proteins, may be (i) one in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue), and such substituted amino acid residue may or may not be one encoded by the genetic code, or (ii) one in which one or more of the amino acid residues includes a substituent group, or (iii) one in which the substrate polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol) or a detectable moiety such as a reporter molecule, or (iv) one in which additional amino acids are fused to the substrate polypeptide, including amino acids that are employed for purification of the substrate polypeptide or a proprotein sequence. Such fragments, derivatives and analogs are deemed to be within the scope of those skilled in the art.

[0075] Certain preferred substrates include phosphoproteins and phosphopeptide sequences that may be tyrosine phosphorylated and/or serine/threonine phosphorylated, for example, as may provide suitable phosphophorylated substrates for dual specificity phosphatases, which are described above. Examples of physiological substrates which may provide phosphoprotein or phosphopeptides sequences for use as PTP substrates, including fragments, variants and derivatives as provided herein, include PDGF receptor, VCP, p130^(cas), EGF receptor, p210 bcr:abl, MAP kinase, Shc, insulin receptor, lck, and T cell receptor zeta chain. A number of non-physiological phosphoproteins and phosphopeptides are also known to be suitable PTP substrates, as described, for example, by Tonks et al. (1991 Meths. Enzymol. 201:427-42; 1988 J. Biol. Chem. 263:6722); these include, as non-limiting examples, poly-[Glu-Tyr], MBP and reduced and carboxyamidomethylated and maleylated lysozyme (RCML, Flint et al., 1993 EMBO J. 12:1937-1946).

[0076] In preferred embodiments the PTP substrate is detectably labeled, and in particularly preferred embodiments the PTP substrate is capable of generating a radioactive or a fluorescent signal. The PTP substrate can be detectably labeled by covalently or non-covalently attaching a suitable reporter molecule or moiety, for example a radionuclide such as ³²P (e.g., Pestka et al., 1999 Protein Expr. Purif. 17:203-14), a radiohalogen such as iodine [¹²⁵I or ¹³¹I] (e.g., Wilbur, 1992 Bioconjug. Chem. 3:433-70), or tritium [³H]; an enzyme; or any of various luminescent (e.g., chemiluminescent) or fluorescent materials (e.g., a fluorophore) selected according to the particular fluorescence detection technique to be employed, as known in the art and based upon the present disclosure. Fluorescent reporter moieties and methods for labeling PTP substrates as provided herein can be found, for example in Haugland (1996 Handbook of Fluorescent Probes and Research Chemicals—Sixth Ed., Molecular Probes, Eugene, Oreg.; 1999 Handbook of Fluorescent Probes and Research Chemicals—Seventh Ed., Molecular Probes, Eugene, Oreg., http://www.probes.com/lit/) and in references cited therein. Particularly preferred for use as such a fluorophore in the subject invention methods are fluorescein, rhodamine, Texas Red, AlexaFluor-594, AlexaFluor-488, Oregon Green, BODIPY-FL, umbelliferone, dichlorotriazinylamine fluorescein, dansyl chloride, phycoerythrin or Cy-5. Examples of suitable enzymes include, but are not limited to, horseradish peroxidase, biotin, alkaline phosphatase, β-galactosidase and acetylcholinesterase. Appropriate luminescent materials include luminol, and suitable radioactive materials include radioactive phosphorus [³²P].

[0077] Antibodies

[0078] Also contemplated by the present invention is the use according to certain embodiments of an antibody that specifically binds to a PTP, which may include peptides, polypeptides, and other non-peptide molecules that specifically bind to a PTP. As used herein, a molecule is said to “specifically bind” to a PTP if it reacts at a detectable level with the PTP, but does not react detectably with peptides containing an unrelated sequence, or a sequence of a different phosphatase. Preferred binding molecules include antibodies, which may be, for example, polyclonal, monoclonal, single chain, chimeric, anti-idiotypic, or CDR-grafted immunoglobulins, or fragments thereof, such as proteolytically generated or recombinantly produced immunoglobulin F(ab′)₂, Fab, Fv, and Fd fragments. Binding properties of an antibody to a PTP may generally be assessed using immunodetection methods including, for example, an enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunoblotting and the like, which may be readily performed by those having ordinary skill in the art. In certain preferred embodiments, the invention method may comprise isolating one or more particular PTPs with an antibody that specifically binds to each phosphatase; such embodiments may include without limitation methodologies for immuno-isolation (e.g., immunoprecipitation, immunoaffinity chromatography) and/or immunodetection (e.g. western blot) of at least one PTP.

[0079] Methods well known in the art may be used to generate antibodies, polyclonal antisera or monoclonal antibodies that are specific for a PTP; a number of PTP-specific antibodies are also commercially available. Antibodies also may be produced as genetically engineered immunoglobulins (Ig) or Ig fragments designed to have desirable properties. For example, by way of illustration and not limitation, antibodies may include a recombinant IgG that is a chimeric fusion protein having at least one variable (V) region domain from a first mammalian species and at least one constant region domain from a second, distinct mammalian species. Most commonly, a chimeric antibody has murine variable region sequences and human constant region sequences. Such a murine/human chimeric immunoglobulin may be “humanized” by grafting the complementarity determining regions (CDRs) derived from a murine antibody, which confer binding specificity for an antigen, into human-derived V region framework regions and human-derived constant regions. Fragments of these molecules may be generated by proteolytic digestion, or optionally, by proteolytic digestion followed by mild reduction of disulfide bonds and alkylation. Alternatively, such fragments may also be generated by recombinant genetic engineering techniques.

[0080] As used herein, an antibody is said to be “immunospecific” or to “specifically bind” a PTP polypeptide if it reacts at a detectable level with PTP, preferably with an affinity constant, K_(a), of greater than or equal to about 10⁴ M⁻¹, more preferably of greater than or equal to about 10⁵ M⁻¹, more preferably of greater than or equal to about 10⁶ M⁻¹, and still more preferably of greater than or equal to about 10⁷ M⁻¹. Affinities of binding partners or antibodies can be readily determined using conventional techniques, for example, those described by Scatchard et al. (Ann. N. Y Acad. Sci. USA 51:660 (1949)) and by surface plasmon resonance (SPR; BIAcore™, Biosensor, Piscataway, N.J.). For surface plasmon resonance, target molecules are immobilized on a solid phase and exposed to ligands in a mobile phase running along a flow cell. If ligand binding to the immobilized target occurs, the local refractive index changes, leading to a change in SPR angle, which can be monitored in real time by detecting changes in the intensity of the reflected light. The rates of change of the surface plasmon resonance signal can be analyzed to yield apparent rate constants for the association and dissociation phases of the binding reaction. The ratio of these values gives the apparent equilibrium constant (affinity). See, e.g., Wolff et al., Cancer Res. 53:2560-2565 (1993).

[0081] Antibodies may generally be prepared by any of a variety of techniques known to those having ordinary skill in the art. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988). In one such technique, an animal is immunized with PTP as an antigen to generate polyclonal antisera. Suitable animals include, for example, rabbits, sheep, goats, pigs, cattle, and may also include smaller mammalian species, such as mice, rats, and hamsters, or other species.

[0082] An immunogen may be comprised of cells expressing PTP, purified or partially purified PTP polypeptides or variants or fragments (e.g., peptides) thereof, or PTP peptides. PTP peptides may be generated by proteolytic cleavage or may be chemically synthesized. For instance, nucleic acid sequences encoding PTP polypeptides are provided herein, such that those skilled in the art may routinely prepare these polypeptides for use as immunogens. Polypeptides or peptides useful for immunization may also be selected by analyzing the primary, secondary, and tertiary structure of PTP according to methods known to those skilled in the art, in order to determine amino acid sequences more likely to generate an antigenic response in a host animal. See, e.g., Novotny, 1991 Mol. Immunol. 28:201-207; Berzofsky, 1985 Science 229:932-40.

[0083] Preparation of the immunogen for injection into animals may include covalent coupling of the PTP polypeptide (or variant or fragment thereof), to another immunogenic protein, for example, a carrier protein such as keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA). In addition, the PTP peptide, polypeptide, or PTP-expressing cells to be used as immunogen may be emulsified in an adjuvant. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988). In general, after the first injection, animals receive one or more booster immunizations according to a preferred schedule that may vary according to, inter alia, the antigen, the adjuvant (if any) and/or the particular animal species. The immune response may be monitored by periodically bleeding the animal, separating the sera out of the collected blood, and analyzing the sera in an immunoassay, such as an ELISA or Ouchterlony diffusion assay, or the like, to determine the specific antibody titer. Once an antibody titer is established, the animals may be bled periodically to accumulate the polyclonal antisera. Polyclonal antibodies that bind specifically to the PTP polypeptide or peptide may then be purified from such antisera, for example, by affinity chromatography using protein A, or the PTP polypeptide, immobilized on a suitable solid support.

[0084] Monoclonal antibodies that specifically bind to PTP polypeptides or fragments or variants thereof, and hybridomas, which are immortal eukaryotic cell lines, that produce monoclonal antibodies having the desired binding specificity, may also be prepared, for example, using the technique of Kohler and Milstein (Nature, 256:495-497; 1976, Eur. J Immunol. 6:511-519 (1975)) and improvements thereto. An animal—for example, a rat, hamster, or preferably mouse—is immunized with a PTP immunogen prepared as described above. Lymphoid cells that include antibody-forming cells, typically spleen cells, are obtained from an immunized animal and may be immortalized by fusion with a drug-sensitized myeloma (e.g., plasmacytoma) cell fusion partner, preferably one that is syngeneic with the immunized animal and that optionally has other desirable properties (e.g., inability to express endogenous Ig gene products). The lymphoid (e.g., spleen) cells and the myeloma cells may be combined for a few minutes with a membrane fusion-promoting agent, such as polyethylene glycol or a nonionic detergent, and then plated at low density on a selective medium that supports the growth of hybridoma cells, but not unfused myeloma cells. A preferred selection media is HAT (hypoxanthine, aminopterin, thymidine). After a sufficient time, usually about one to two weeks, colonies of cells are observed. Single colonies are isolated, and antibodies produced by the cells may be tested for binding activity to the PTP polypeptide, or variant or fragment thereof. Hybridomas producing monoclonal antibodies with high affinity and specificity for a PTP antigen are preferred. Hybridomas that produce monoclonal antibodies that specifically bind to a PTP polypeptide or variant or fragment thereof are therefore contemplated by the present invention.

[0085] Monoclonal antibodies may be isolated from the supernatants of hybridoma cultures. An alternative method for production of a murine monoclonal antibody is to inject the hybridoma cells into the peritoneal cavity of a syngeneic mouse, for example, a mouse that has been treated (e.g., pristane-primed) to promote formation of ascites fluid containing the monoclonal antibody. Contaminants may be removed from the subsequently (usually within 1-3 weeks) harvested ascites fluid by conventional techniques, such as chromatography, gel filtration, precipitation, extraction, or the like. For example, antibodies may be purified by affinity chromatography using an appropriate ligand selected based on particular properties of the monoclonal antibody (e.g., heavy or light chain isotype, binding specificity, etc.). Examples of a suitable ligand, immobilized on a solid support, include Protein A, Protein G, an anti-constant region (light chain or heavy chain) antibody, an anti-idiotype antibody and a PTP polypeptide or fragment or variant thereof.

[0086] Human monoclonal antibodies may be generated by any number of techniques with which those having ordinary skill in the art will be familiar. Such methods include but are not limited to, Epstein Barr Virus (EBV) transformation of human peripheral blood cells (e.g., containing B lymphocytes), in vitro immunization of human B cells, fusion of spleen cells from immunized transgenic mice carrying human immunoglobulin genes inserted by yeast artificial chromosomes (YAC), isolation from human immunoglobulin V region phage libraries, or other procedures as known in the art and based on the disclosure herein.

[0087] For example, one method for generating human monoclonal antibodies includes immortalizing human peripheral blood cells by EBV transformation. See, e.g., U.S. Pat. No. 4,464,456. An immortalized cell line producing a monoclonal antibody that specifically binds to a PTP polypeptide (or a variant or fragment thereof) can be identified by immunodetection methods as provided herein, for example, an ELISA, and then isolated by standard cloning techniques. Another method to generate human monoclonal antibodies, in vitro immunization, includes priming human splenic B cells with antigen, followed by fusion of primed B cells with a heterohybrid fusion partner. See, e.g., Boerner et al., 1991 J. Immunol. 147:86-95.

[0088] Still another method for the generation of human PTP-specific monoclonal antibodies and polyclonal antisera for use in the present invention relates to transgenic mice. See, e.g., U.S. Pat. No. 5,877,397; Bruggemann et al., 1997 Curr. Opin. Biotechnol. 8:455-58; Jakobovits et al., 1995 Ann. N. Y. Acad. Sci. 764:525-35. In these mice, human immunoglobulin heavy and light chain genes have been artificially introduced by genetic engineering in germline configuration, and the endogenous murine immunoglobulin genes have been inactivated. See, e.g., Bruggemann et al., 1997 Curr. Opin. Biotechnol. 8:455-58. For example, human immunoglobulin transgenes may be mini-gene constructs, or transloci on yeast artificial chromosomes, which undergo B cell-specific DNA rearrangement and hypermutation in the mouse lymphoid tissue. See, Bruggemann et al., 1997 Curr. Opin. Biotechnol. 8:455-58. Human monoclonal antibodies specifically binding to PTP may be obtained by immunizing the transgenic animals, fusing spleen cells with myeloma cells, selecting and then cloning cells producing antibody, as described above. Polyclonal sera containing human antibodies may also be obtained from the blood of the immunized animals.

[0089] Chimeric antibodies, specific for a PTP, including humanized antibodies, may also be generated according to the present invention. A chimeric antibody has at least one constant region domain derived from a first mammalian species and at least one variable region domain derived from a second, distinct mammalian species. See, e.g., Morrison et al., 1984, Proc. Natl. Acad. Sci. USA, 81:6851-55. In preferred embodiments, a chimeric antibody may be constructed by cloning the polynucleotide sequence that encodes at least one variable region domain derived from a non-human monoclonal antibody, such as the variable region derived from a murine, rat, or hamster monoclonal antibody, into a vector containing a nucleic acid sequence that encodes at least one human constant region. See, e.g., Shin et al., 1989 Methods Enzymol. 178:459-76; Walls et al., 1993 Nucleic Acids Res. 21:2921-29. By way of example, the polynucleotide sequence encoding the light chain variable region of a murine monoclonal antibody may be inserted into a vector containing a nucleic acid sequence encoding the human kappa light chain constant region sequence. In a separate vector, the polynucleotide sequence encoding the heavy chain variable region of the monoclonal antibody may be cloned in frame with sequences encoding the human IgG1 constant region. The particular human constant region selected may depend upon the effector functions desired for the particular antibody (e.g., complement fixing, binding to a particular Fc receptor, etc.). Another method known in the art for generating chimeric antibodies is homologous recombination (e.g., U.S. Pat. No. 5,482,856). Preferably, the vectors will be transfected into eukaryotic cells for stable expression of the chimeric antibody.

[0090] A non-human/human chimeric antibody may be further genetically engineered to create a “humanized” antibody. Such a humanized antibody may comprise a plurality of CDRs derived from an immunoglobulin of a non-human mammalian species, at least one human variable framework region, and at least one human immunoglobulin constant region. Humanization may in certain embodiments provide an antibody that has decreased binding affinity for a PTP when compared, for example, with either a non-human monoclonal antibody from which a PTP binding variable region is obtained, or a chimeric antibody having such a V region and at least one human C region, as described above. Useful strategies for designing humanized antibodies may therefore include, for example by way of illustration and not limitation, identification of human variable framework regions that are most homologous to the non-human framework regions of the chimeric antibody. Without wishing to be bound by theory, such a strategy may increase the likelihood that the humanized antibody will retain specific binding affinity for a PTP, which in some preferred embodiments may be substantially the same affinity for a PTP polypeptide or variant or fragment thereof, and in certain other preferred embodiments may be a greater affinity for PTP. See, e.g., Jones et al., 1986 Nature 321:522-25; Riechmann et al., 1988 Nature 332:323-27. Designing such a humanized antibody may therefore include determining CDR loop conformations and structural determinants of the non-human variable regions, for example, by computer modeling, and then comparing the CDR loops and determinants to known human CDR loop structures and determinants. See, e.g., Padlan et al., 1995 FASEB 9:133-39; Chothia et al., 1989 Nature, 342:377-383. Computer modeling may also be used to compare human structural templates selected by sequence homology with the non-human variable regions. See, e.g., Bajorath et al., 1995 Ther. Immunol. 2:95-103; EP-0578515-A3. If humanization of the non-human CDRs results in a decrease in binding affinity, computer modeling may aid in identifying specific amino acid residues that could be changed by site-directed or other mutagenesis techniques to partially, completely or supra-optimally (i.e., increase to a level greater than that of the non-humanized antibody) restore affinity. Those having ordinary skill in the art are familiar with these techniques, and will readily appreciate numerous variations and modifications to such design strategies.

[0091] Within certain embodiments, the use of antigen-binding fragments of antibodies may be preferred. Such fragments include Fab fragments or F(ab′)₂ fragments, which may be prepared by proteolytic digestion with papain or pepsin, respectively. The antigen binding fragments may be separated from the Fc fragments by affinity chromatography, for example, using immobilized protein A or protein G, or immobilized PTP polypeptide, or a suitable variant or fragment thereof. Those having ordinary skill in the art can routinely and without undue experimentation determine what is a suitable variant or fragment based on characterization of affinity purified antibodies obtained, for example, using immunodetection methods as provided herein. An alternative method to generate Fab fragments includes mild reduction of F(ab′)₂ fragments followed by alkylation. See, e.g., Weir, Handbook of Experimental Immunology, 1986, Blackwell Scientific, Boston.

[0092] According to certain embodiments, non-human, human, or humanized heavy chain and light chain variable regions of any of the above described Ig molecules may be constructed as single chain Fv (sFv) polypeptide fragments (single chain antibodies). See, e.g., Bird et al., 1988 Science 242:423-426; Huston et al., 1988 Proc. Natl. Acad. Sci. USA 85:5879-5883. Multi-functional sFv fusion proteins may be generated by linking a polynucleotide sequence encoding an sFv polypeptide in-frame with at least one polynucleotide sequence encoding any of a variety of known effector proteins. These methods are known in the art, and are disclosed, for example, in EP-B1-0318554, U.S. Pat. No. 5,132,405, U.S. Pat. No. 5,091,513, and U.S. Pat. No. 5,476,786. By way of example, effector proteins may include immunoglobulin constant region sequences. See, e.g., Hollenbaugh et al., 1995 J. Immunol. Methods 188:1-7. Other examples of effector proteins are enzymes. As a non-limiting example, such an enzyme may provide a biological activity for therapeutic purposes (see, e.g., Siemers et al., 1997 Bioconjug. Chem. 8:510-19), or may provide a detectable activity, such as horseradish peroxidase-catalyzed conversion of any of a number of well-known substrates into a detectable product, for diagnostic uses. Still other examples of sFv fusion proteins include Ig-toxin fusions, or immunotoxins, wherein the sFv polypeptide is linked to a toxin. Those having ordinary skill in the art will appreciate that a wide variety of polypeptide sequences have been identified that, under appropriate conditions, are toxic to cells. As used herein, a toxin polypeptide for inclusion in an immunoglobulin-toxin fusion protein may be any polypeptide capable of being introduced to a cell in a manner that compromises cell survival, for example, by directly interfering with a vital function or by inducing apoptosis. Toxins thus may include, for example, ribosome-inactivating proteins, such as Pseudomonas aeruginosa exotoxin A, plant gelonin, bryodin from Bryonia dioica, or the like. See, e.g., Thrush et al., 1996 Annu. Rev. Immunol. 14:49-71; Frankel et al., 1996 Cancer Res. 56:926-32. Numerous other toxins, including chemotherapeutic agents, anti-mitotic agents, antibiotics, inducers of apoptosis (or “apoptogens”, see, e.g., Green and Reed, 1998, Science 281:1309-1312), or the like, are known to those familiar with the art, and the examples provided herein are intended to be illustrative without limiting the scope and spirit of the invention.

[0093] The sFv may, in certain embodiments, be fused to peptide or polypeptide domains that permit detection of specific binding between the fusion protein and antigen (e.g., a PTP). For example, the fusion polypeptide domain may be an affinity tag polypeptide. Binding of the sFv fusion protein to a binding partner (e.g., a PTP) may therefore be detected using an affinity polypeptide or peptide tag, such as an avidin, streptavidin or a His (e.g., polyhistidine) tag, by any of a variety of techniques with which those skilled in the art will be familiar. Detection techniques may also include, for example, binding of an avidin or streptavidin fusion protein to biotin or to a biotin mimetic sequence (see, e.g., Luo et al., 1998 J. Biotechnol. 65:225 and references cited therein), direct covalent modification of a fusion protein with a detectable moiety (e.g., a labeling moiety), non-covalent binding of the fusion protein to a specific labeled reporter molecule, enzymatic modification of a detectable substrate by a fusion protein that includes a portion having enzyme activity, or immobilization (covalent or non-covalent) of the fusion protein on a solid-phase support.

[0094] The sFv fusion protein of the present invention, comprising a PTP-specific immunoglobulin-derived polypeptide fused to another polypeptide such as an effector peptide having desirable affinity properties, may therefore include, for example, a fusion protein wherein the effector peptide is an enzyme such as glutathione-S-transferase. As another example, sFv fusion proteins may also comprise a PTP-specific Ig polypeptide fused to a Staphylococcus aureus protein A polypeptide; protein A encoding nucleic acids and their use in constructing fusion proteins having affinity for immunoglobulin constant regions are disclosed generally, for example, in U.S. Pat. No. 5,100,788. Other useful affinity polypeptides for construction of sFv fusion proteins may include streptavidin fusion proteins, as disclosed, for example, in WO 89/03422; U.S. Pat. Nos. 5,489,528; 5,672,691; WO 93/24631; U.S. Pat. Nos. 5,168,049; 5,272,254 and elsewhere, and avidin fusion proteins (see, e.g., EP 511,747). As provided herein, sFv polypeptide sequences may be fused to fusion polypeptide sequences, including effector protein sequences, that may include full length fusion polypeptides and that may alternatively contain variants or fragments thereof.

[0095] An additional method for selecting antibodies that specifically bind to a PTP polypeptide or variant or fragment thereof is by phage display. See, e.g., Winter et al., 1994 Annul. Rev. Immunol. 12:433-55; Burton et al., 1994 Adv. Immunol. 57:191-280. Human or murine immunoglobulin variable region gene combinatorial libraries may be created in phage vectors that can be screened to select Ig fragments (Fab, Fv, sFv, or multimers thereof) that bind specifically to a PTP polypeptide or variant or fragment thereof. See, e.g., U.S. Pat. No. 5,223,409; Huse et al., 1989 Science 246:1275-81; Kang et al., 1991 Proc. Natl. Acad. Sci. USA 88:4363-66; Hoogenboom et al., 1992 J. Molec. Biol. 227:381-388; Schlebusch et al., 1997 Hybridoma 16:47-52 and references cited therein. For example, a library containing a plurality of polynucleotide sequences encoding Ig variable region fragments may be inserted into the genome of a filamentous bacteriophage, such as M13 or a variant thereof, in frame with the sequence encoding a phage coat protein, for instance, gene III or gene VIII of M13, to create an M13 fusion protein. A fusion protein may be a fusion of the coat protein with the light chain variable region domain and/or with the heavy chain variable region domain.

[0096] According to certain embodiments, immunoglobulin Fab fragments may also be displayed on the phage particle, as follows. Polynucleotide sequences encoding Ig constant region domains may be inserted into the phage genome in frame with a coat protein. The phage coat fusion protein may thus be fused to an Ig light chain or heavy chain fragment (Fd). For example, from a human Ig library, the polynucleotide sequence encoding the human kappa constant region may be inserted into a vector in frame with the sequence encoding at least one of the phage coat proteins. Additionally or alternatively, the polynucleotide sequence encoding the human IgG1 CH1 domain may be inserted in frame with the sequence encoding at least one other of the phage coat proteins. A plurality of polynucleotide sequences encoding variable region domains (e.g., derived from a DNA library) may then be inserted into the vector in frame with the constant region-coat protein fusions, for expression of Fab fragments fused to a bacteriophage coat protein.

[0097] Phage that display an Ig fragment (e.g., an Ig V-region or Fab) that binds to a PTP polypeptide may be selected by mixing the phage library with PTP or a variant or a fragment thereof, or by contacting the phage library with a PTP polypeptide immobilized on a solid matrix under conditions and for a time sufficient to allow binding. Unbound phage are removed by a wash, which typically may be a buffer containing salt (e.g., NaCl) at a low concentration, preferably with less than 100 mM NaCl, more preferably with less than 50 mM NaCl, most preferably with less than 10 mM NaCl, or, alternatively, a buffer containing no salt. Specifically bound phage are then eluted with an NaCl-containing buffer, for example, by increasing the salt concentration in a step-wise manner. Typically, phage that bind the PTP with higher affinity will require higher salt concentrations to be released. Eluted phage may be propagated in an appropriate bacterial host, and generally, successive rounds of PTP binding and elution can be repeated to increase the yield of phage expressing PTP-specific immunoglobulin. Combinatorial phage libraries may also be used for humanization of non-human variable regions. See, e.g., Rosok et al., 1996 J. Biol. Chem. 271:22611-18; Rader et al., 1998 Proc. Natl. Acad. Sci. USA 95:8910-15. The DNA sequence of the inserted immunoglobulin gene in the phage so selected may be determined by standard techniques. See, Sambrook et al., 1989 Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press. The affinity selected Ig-encoding sequence may then be cloned into another suitable vector for expression of the Ig fragment or, optionally, may be cloned into a vector containing Ig constant regions, for expression of whole immunoglobulin chains.

[0098] Phage display techniques may also be used to select polypeptides, peptides or single chain antibodies that bind to PTP. For examples of suitable vectors having multicloning sites into which candidate nucleic acid molecules (e.g., DNA) encoding such peptides or antibodies may be inserted, see, e.g., McLafferty et al., Gene 128:29-36, 1993; Scott et al., 1990 Science 249:386-390; Smith et al., 1993 Methods Enzymol. 217:228-257; Fisch et al., 1996, Proc. Natl. Acad. Sci. USA 93:7761-66. The inserted DNA molecules may comprise randomly generated sequences, or may encode variants of a known peptide or polypeptide domain that specifically binds to a PTP polypeptide, or variant or fragment thereof, as provided herein. Generally, the nucleic acid insert encodes a peptide of up to 60 amino acids, more preferably a peptide of 3 to 35 amino acids, and still more preferably a peptide of 6 to 20 amino acids. The peptide encoded by the inserted sequence is displayed on the surface of the bacteriophage. Phage expressing a binding domain for a PTP polypeptide may be selected on the basis of specific binding to an immobilized PTP polypeptide as described above. As provided herein, well-known recombinant genetic techniques may be used to construct fusion proteins containing the fragment thereof. For example, a polypeptide may be generated that comprises a tandem array of two or more similar or dissimilar affinity selected PTP binding peptide domains, in order to maximize binding affinity for PTP of the resulting product.

[0099] In certain other embodiments, the invention contemplates PTP-specific antibodies that are multimeric antibody fragments. Useful methodologies are described generally, for example in Hayden et al. 1997, Curr Opin. Immunol. 9:201-12; Coloma et al., 1997 Nat. Biotechnol. 15:159-63). For example, multimeric antibody fragments may be created by phage techniques to form miniantibodies (U.S. Pat. No. 5,910,573) or diabodies (Holliger et al., 1997, Cancer Immunol. Immunother. 45:128-130). Multimeric fragments may be generated that are multimers of a PTP-specific Fv, or that are bispecific antibodies comprising a PTP-specific Fv noncovalently associated with a second Fv having a different antigen specificity. See, e.g., Koelemij et al., 1999 J. Immunother. 22:514-24. As another example, a multimeric antibody may comprise a bispecific antibody having two single chain antibodies or Fab fragments. According to certain related embodiments, a first Ig fragment may be specific for a first antigenic determinant on a PTP polypeptide (or variant or fragment thereof), while a second Ig fragment may be specific for a second antigenic determinant of the PTP polypeptide. Alternatively, in certain other related embodiments, a first immunoglobulin fragment may be specific for an antigenic determinant on a PTP polypeptide or variant or fragment thereof, and a second immunoglobulin fragment may be specific for an antigenic determinant on a second, distinct (i.e., non-PTP) molecule. Also contemplated are bispecific antibodies that specifically bind PTP, wherein at least one antigen-binding domain is present as a fusion protein.

[0100] Introducing amino acid mutations into PTP-binding immunoglobulin molecules may be useful to increase the specificity or affinity for PTP, or to alter an effector function. Immunoglobulins with higher affinity for PTP may be generated by site-directed mutagenesis of particular residues. Computer assisted three-dimensional molecular modeling may be employed to identify the amino acid residues to be changed, in order to improve affinity for the PTP polypeptide. See, e.g., Mountain et al., 1992, Biotechnol. Genet. Eng. Rev. 10: 1-142. Alternatively, combinatorial libraries of CDRs may be generated in M13 phage and screened for immunoglobulin fragments with improved affinity. See, e.g., Glaser et al., 1992, J. Immunol. 149:3903-3913; Barbas et al., 1994 Proc. Natl. Acad. Sci. USA 91:3809-13; U.S. Pat. No. 5,792,456).

[0101] Effector functions may also be altered by site-directed mutagenesis. See, e.g., Duncan et al., 1988 Nature 332:563-64; Morgan et al., 1995 Immunology 86:319-24; Eghtedarzedeh-Kondri et al., 1997 Biotechniques 23:830-34. For example, mutation of the glycosylation site on the Fe portion of the immunoglobulin may alter the ability of the immunoglobulin to fix complement. See, e.g., Wright et al., 1997 Trends Biotechnol. 15:26-32. Other mutations in the constant region domains may alter the ability of the immunoglobulin to fix complement, or to effect antibody-dependent cellular cytotoxicity. See, e.g., Duncan et al., 1988 Nature 332:563-64; Morgan et al., 1995 Immunology 86:319-24; Sensel et al., 1997 Mol. Immunol. 34:1019-29.

[0102] The nucleic acid molecules encoding an antibody or fragment thereof that specifically binds PTP, as described herein, may be propagated and expressed according to any of a variety of well-known procedures for nucleic acid excision, ligation, transformation and transfection. Thus, in certain embodiments expression of an antibody fragment may be preferred in a prokaryotic host, such as Escherichia coli (see, e.g., Pluckthun et al., 1989 Methods Enzymol. 178:497-515). In certain other embodiments, expression of the antibody or a fragment thereof may be preferred in a eukaryotic host cell, including yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris), animal cells (including mammalian cells) or plant cells. Examples of suitable animal cells include, but are not limited to, myeloma, COS, CHO, or hybridoma cells. Examples of plant cells include tobacco, corn, soybean, and rice cells. By methods known to those having ordinary skill in the art and based on the present disclosure, a nucleic acid vector may be designed for expressing foreign sequences in a particular host system, and then polynucleotide sequences encoding the PTP binding antibody (or fragment thereof) may be inserted. The regulatory elements will vary according to the particular host.

[0103] A PTP-binding immunoglobulin (or fragment thereof) as described herein may contain a detectable moiety or label such as an enzyme, cytotoxic agent or other reporter molecule, including a dye, radionuclide, luminescent group, fluorescent group, or biotin, or the like. The PTP-specific immunoglobulin or fragment thereof may be radiolabeled for diagnostic or therapeutic applications. Techniques for radiolabeling of antibodies are known in the art. See, e.g., Adams 1998 In Vivo 12:11-21; Hiltunen 1993 Acta Oncol. 32:831-9. Therapeutic applications are described in greater detail below and may include use of the PTP-binding antibody (or fragment thereof) in conjunction with other therapeutic agents. The antibody or fragment may also be conjugated to a cytotoxic agent as known in the art and provided herein, for example, a toxin, such as a ribosome-inactivating protein, a chemotherapeutic agent, an anti-mitotic agent, an antibiotic or the like.

[0104] As provided herein and according to methodologies well known in the art, polyclonal and monoclonal antibodies may be used for the affinity isolation of PTP polypeptides. See, e.g., Hermanson et al., Immobilized Affinity Ligand Techniques, Academic Press, Inc. New York, 1992. Briefly, an antibody (or antigen-binding fragment thereof) may be immobilized on a solid support material, which is then contacted with a sample comprising the polypeptide of interest (e.g., a PTP). Following separation from the remainder of the sample, the polypeptide is then released from the immobilized antibody.

[0105] Methods For Detecting PTP Expression

[0106] Certain embodiments of the present invention provide methods that employ antibodies raised against PTP for assay purposes. Certain assays involve using an antibody or other agent to detect the presence or absence of PTP, or proteolytic fragments thereof. Assays may generally be performed using any of a variety of samples obtained from a biological source, as provided herein.

[0107] To detect a PTP protein, the reagent is typically an antibody, as provided herein. There are a variety of assay formats known to those having ordinary skill in the art for using an antibody to detect a polypeptide in a sample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. For example, the assay may be performed in a Western blot format, wherein a protein preparation from the biological sample is resolved by gel electrophoresis, transferred to a suitable membrane and allowed to react with the antibody. The presence of the antibody on the membrane may then be detected using a suitable detection reagent, as described below. In certain embodiments of the present invention, this format may be preferred to determine, establish or confirm the specific identity of a PTP that is identified as being reversibly modified or reversibly oxidized in a cell.

[0108] In another embodiment, isolation of a PTP may involve the use of antibody immobilized on a solid support to bind to the target PTP and remove it from the remainder of the sample. The bound PTP may then be detected using a second antibody or reagent that contains a reporter group. Alternatively, a competitive assay may be utilized, in which a PTP polypeptide is labeled with a reporter group and allowed to bind to the immobilized antibody after incubation of the antibody with the sample. The extent to which components of the sample inhibit the binding of the labeled polypeptide to the antibody is indicative of the reactivity of the sample with the immobilized antibody, and as a result, indicative of the level of PTP in the sample.

[0109] The solid support may be any material known to those having ordinary skill in the art to which the antibody may be attached, such as a test well in a microtiter plate, a nitrocellulose filter or another suitable membrane. Alternatively, the support may be a bead or disc, such as glass, fiberglass, latex or a plastic such as polystyrene or polyvinylchloride. The antibody may be immobilized on the solid support using a variety of techniques known to those in the art, which are amply described in the patent and scientific literature.

[0110] In certain embodiments, the assay for detection of PTP in a sample is a two-antibody sandwich assay. This assay may be performed by first contacting an antibody that has been immobilized on a solid support, commonly the well of a microtiter plate, with the biological sample, such that PTP within the sample is allowed to bind to the immobilized antibody (a 30 minute incubation time at room temperature is generally sufficient). Unbound sample is then removed from the immobilized PTP/antibody complexes and a second antibody (containing a reporter group such as an enzyme, dye, radionuclide, luminescent group, fluorescent group or biotin) capable of binding to a different site on the PTP is added. The amount of second antibody that remains bound to the solid support is then determined using a method appropriate for the specific reporter group. For radioactive groups, scintillation counting or autoradiographic methods are generally appropriate. Spectroscopic methods may be used to detect dyes, luminescent groups and fluorescent groups. Biotin may be detected using avidin, coupled to a different reporter group (commonly a radioactive or fluorescent group or an enzyme). Enzyme reporter groups may generally be detected by the addition of substrate (generally for a specific period of time), followed by spectroscopic or other analysis of the reaction products. Standards and standard additions may be used to determine the level of PTP in a sample, using well known techniques.

[0111] In a related aspect of the present invention, kits for detecting a reversibly modified PTP, and for determining PTP phosphatase activity, are provided. Such kits may be designed for detecting the level of PTP, or may detect phosphatase activity of PTP in a direct phosphatase assay or a coupled phosphatase assay. In general, the kits of the present invention comprise one or more containers enclosing elements, such as reagents or buffers, to be used in the assay. A kit for detecting the level of a PTP typically contains a reagent that specifically binds to the PTP protein; the reagent is typically an antibody. Such kits also contain a reporter group suitable for direct or indirect detection of the reagent (i.e., the reporter group may be covalently bound to the reagent or may be bound to a second molecule, such as Protein A, Protein G, immunoglobulin or lectin, which is itself capable of binding to the reagent). Suitable reporter groups include, but are not limited to, enzymes (e.g., horseradish peroxidase), substrates, cofactors, inhibitors, dyes, radionuclides, luminescent groups, fluorescent groups and biotin. Such reporter groups may be used to directly or indirectly detect binding of the reagent to a sample component using standard methods known to those having ordinary skill in the art.

[0112] Kits for detecting PTP activity typically comprise a PTP substrate in combination with a suitable buffer. PTP activity may be specifically detected by performing an immunoprecipitation step with a PTP-specific antibody prior to performing a phosphatase assay as described above. Other reagents for use in detecting dephosphorylation of substrate may also be provided.

[0113] Screening Assays for Agents

[0114] Where a PTP is identified that is a reversibly modified/oxidized component of a biological signaling pathway as provided herein, by using the methods of the present invention, it is further contemplated that in certain further embodiments the invention provides a screening assay for an agent that alters an inducible biological signaling pathway. According to such assays, a cell comprising the PTP (and hence the inducible pathway wherein the PTP is reversibly modified) is contacted with a stimulus that induces the pathway in the absence and presence of a candidate agent, under conditions permissive for induction of the pathway by the stimulus. PTPs are then isolated from the cell in the presence of a sulfhydryl-reactive agent that is capable of covalently (e.g., irreversibly) modifying a sulfhydryl group of the PTP active site invariant cysteine where, as described herein, the signaling pathway component PTP that is reversibly modified (e.g., oxidized) is protected from inactivation by such sulfhydryl agent, and PTP catalytic activity is determined by any of a variety of established methods, as also provided herein, after the reversibly modified PTP is reactivated by reversal of the modification (e.g., under reducing conditions). Decreased substrate dephosphorylation when the pathway is induced in the presence of the candidate agent, relative to the level of dephosphorylation when induction transpires in the absence of the candidate agent, indicates that the agent is an inhibitor or antagonist (e.g., results in PTP catalytic activity in the cell that is decreased in a statistically significant manner) of the reversibly modified PTP. Conversely, increased substrate dephosphorylation when the pathway is induced in the presence of the candidate agent, relative to the level of dephosphorylation when induction transpires in the absence of the candidate agent, indicates that the agent is a potentiator or agonist (i.e., an activity enhancer) of the reversibly modified PTP (e.g., results in PTP catalytic activity in the cell that is increased in a statistically significant manner). The assays of this embodiment of the invention therefore provide a method for identifying an agent that alters an inducible biological signaling pathway, which agent will be useful where specific manipulation of or intervention in a particular stimulus-inducible pathway may be desirable.

[0115] Candidate agents for use in a method for identifying an agent that alters (e.g., increases or decreases in a statistically significant manner at least one phenotype associated with pathway induction) an inducible biological signaling pathway according to the present invention may be provided as “libraries” or collections of compounds, compositions or molecules. Such molecules typically include compounds known in the art as “small molecules” and having molecular weights less than 10⁵ daltons, preferably less than 10⁴ daltons and still more preferably less than 10³ daltons. For example, members of a library of test compounds can be administered to a plurality of samples, each containing at least one biological sample comprising a cell that comprises a PTP which has been identified as a reversibly modified (e.g., oxidized) component of an inducible biological signaling pathway as provided herein, and then assayed for their ability to enhance or inhibit dephosphorylation of a PTP substrate by the PTP. Compounds so identified as capable of influencing PTP function (e.g., phosphotyrosine and/or phosphoserine/threonine dephosphorylation) are valuable for therapeutic and/or diagnostic purposes, since they permit treatment and/or detection of diseases associated with PTP activity. Such compounds are also valuable in research directed to molecular signaling mechanisms that involve PTP, and to refinements in the discovery and development of future PTP compounds exhibiting greater specificity.

[0116] Candidate agents further may be provided as members of a combinatorial library, which preferably includes synthetic agents prepared according to a plurality of predetermined chemical reactions performed in a plurality of reaction vessels. For example, various starting compounds may be prepared employing one or more of solid-phase synthesis, recorded random mix methodologies and recorded reaction split techniques that permit a given constituent to traceably undergo a plurality of permutations and/or combinations of reaction conditions. The resulting products comprise a library that can be screened followed by iterative selection and synthesis procedures, such as a synthetic combinatorial library of peptides (see e.g., PCT/US91/08694, PCT/US91/04666, which are hereby incorporated by reference in their entireties) or other compositions that may include small molecules as provided herein (see e.g., PCT/US94/08542, EP 0774464, U.S. Pat. Nos. 5,798,035, 5,789,172, 5,751,629, which are hereby incorporated by reference in their entireties). Those having ordinary skill in the art will appreciate that a diverse assortment of such libraries may be prepared according to established procedures, and tested using PTP according to the present disclosure.

[0117] Therapeutic Methods

[0118] One or more agents capable of altering an inducible biological signaling pathway and identified according to the above described methods may also be used to modulate (e.g., inhibit or potentiate) PTP activity in a patient. As used herein, a “patient” may be any mammal, including a human, and may be afflicted with a condition associated with PTP activity or may be free of detectable disease. Accordingly, the treatment may be of an existing disease or may be prophylactic. Conditions associated with PTP activity include any disorder associated with cell proliferation, including cancer, graft-versus-host disease (GVHD), autoimmune diseases, allergy or other conditions in which immunosuppression may be involved, metabolic diseases, abnormal cell growth or proliferation and cell cycle abnormalities.

[0119] For administration to a patient, one or more modulating agents are generally formulated as a pharmaceutical composition. A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, which additionally comprises a physiologically acceptable carrier (i.e., a non-toxic material that does not interfere with the activity of the active ingredient). Such compositions may be in the form of a solid, liquid or gas (aerosol). Alternatively, compositions of the present invention may be formulated as a lyophilizate or compounds may be encapsulated within liposomes using well known technology. Pharmaceutical compositions within the scope of the present invention may also contain other components, which may be biologically active or inactive. Such components include, but are not limited to, buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, stabilizers, dyes, flavoring agents, and suspending agents and/or preservatives.

[0120] Any suitable carrier known to those of ordinary skill in the art may be employed in the pharmaceutical compositions of the present invention. Carriers for therapeutic use are well known, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro ed. 1985). In general, the type of carrier is selected based on the mode of administration. Pharmaceutical compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, intrathecal, rectal, vaginal, sublingual or parenteral administration, including subcutaneous, intravenous, intramuscular, intrastemal, intracavernous, intrameatal or intraurethral injection or infusion. For parenteral administration, the carrier preferably comprises water, saline, alcohol, a fat, a wax or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose, ethyl cellulose, glucose, sucrose and/or magnesium carbonate, may be employed.

[0121] A pharmaceutical composition (e.g., for oral administration or delivery by injection) may be in the form of a liquid (e.g., an elixir, syrup, solution, emulsion or suspension). A liquid pharmaceutical composition may include, for example, one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.

[0122] The compositions described herein may be formulated for sustained release (i.e., a formulation such as a capsule or sponge that effects a slow release of compound following administration). Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain an agent dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of active compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.

[0123] Within a pharmaceutical composition, a PTP modulating agent may be linked to any of a variety of compounds. For example, such an agent may be linked to a targeting moiety (e.g., a monoclonal or polyclonal antibody, a protein or a liposome) that facilitates the delivery of the agent to the target site. As used herein, a “targeting moiety” may be any substance (such as a compound or cell) that, when linked to an agent enhances the transport of the agent to a target cell or tissue, thereby increasing the local concentration of the agent. Targeting moieties include antibodies or fragments thereof, receptors, ligands and other molecules that bind to cells of, or in the vicinity of, the target tissue. An antibody targeting agent may be an intact (whole) molecule, a fragment thereof, or a functional equivalent thereof. Examples of antibody fragments are F(ab′)₂, −Fab′, Fab and F[v] fragments, which may be produced by conventional methods or by genetic or protein engineering. Linkage is generally covalent and may be achieved by, for example, direct condensation or other reactions, or by way of bi- or multi-functional linkers. Targeting moieties may be selected based on the cell(s) or tissue(s) toward which the agent is expected to exert a therapeutic benefit.

[0124] Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dosage and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. In general, an appropriate dosage and treatment regimen provides the agent(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival). For prophylactic use, a dose should be sufficient to prevent, delay the onset of or diminish the severity of a disease associated with cell proliferation.

[0125] Optimal dosages may generally be determined using experimental models and/or clinical trials. In general, the amount of polypeptide present in a dose, or produced in situ by DNA present in a dose, ranges from about 0.01 μg to about 100 μg per kg of host, typically from about 0.1 μg to about 10 μg. The use of the minimum dosage that is sufficient to provide effective therapy is usually preferred. Patients may generally be monitored for therapeutic or prophylactic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those having ordinary skill in the art. Suitable dose sizes will vary with the size of the patient, but will typically range from about 10 mL to about 500 mL for 10-60 kg animal.

[0126] The following Examples are offered for the purpose of illustrating the present invention and are not to be construed to limit the scope of this invention.

EXAMPLES Example 1 Reversible Inactivation of PTPs in Rat-1 Cells by Hydrogen Peroxide

[0127] Cell culture, transient transfection, immunoprecipitation and immunoblotting: Rat-1 fibroblasts (American Type Culture Collection, Manassas, Va.) were routinely maintained in DMEM supplemented with 10% FBS, 1% glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin (all reagents Sigma, St. Louis, Mo., unless otherwise noted). For stimulation with H₂O₂ and peptide growth factors, cells were plated in media containing 10% FBS for 48 hours, then serum-starved for 16 hours before treatment. For transient transfection, Rat-1 cells were plated in DMEM medium supplemented with 10% FBS, for 16 hours. The culture medium was replaced by OptiMEM™ (Invitrogen Life Technologies, Inc. Gaithersburg, Md.) without serum, then plasmid (5 μg/dish) was introduced into cells by LipofectAMINE™ and PLUS™ reagents (Life Technologies), according to the manufacture's recommendations. The transfection efficiency was routinely 40%.

[0128] For immunoprecipitation, cells were rinsed with ice-cold PBS, then lysed in ice-cold 20 mM Hepes (pH 7.5), 1% NP-40, 150 mM NaCl, 10% glycerol, 200 μM Na₃VO₅ and protease inhibitors (25 μg/ml of aprotinin and leupeptin). Antibodies having the indicated specificities were purchased from the following suppliers: SHP-1 (C-19), SHP-2 (C-18) and P13K (Z-8), Santa Cruz Biotecnology, Santa Cruz, Calif.; phospho-MAPK and MAPK, Cell Signaling, Inc. (Beverly, Mass.); GAP, BD Transduction Laboratories (Lexington, Ky.); and pTyr mAb PT66, Sigma, St. Louis, Mo. The anti-pTyr antibody G104 was described previously (Garton et al., 1997 Oncogene 15, 877-885). Anti-PDGFRββ antibody (Ab-X) was a gift from Dr. Daniel DiMaio at Yale University (Irusta and DiMaio, 1998 EMBO J. 17, 6912-6923). Anti-human G-CSF receptor (G-CSFR) antibody was provided by Dr. Toshio Hirano at Osaka University, Japan (Fukada et al., 1996 Immunity 5, 449-460). Lysate (400 μg) was incubated with 5 μg of antibody conjugated to protein A/G-Sepharose (Amersham Pharmacia, Arlington Heights, Ill.) for 2 hours at 4° C. For immunoblotting, aliquots of total lysates (30 μg per sample) or immunoprecipitates were subjected to SDS-PAGE and transferred to nitrocellulose filters, which were incubated with appropriate primary and secondary antibodies and the specific signals were visualized by the ECL detection system (Amersham Pharmacia).

[0129] To determine whether ROS stimulated intracellular tyrosine phosphorylation through the oxidation and inhibition of cellular PTPs, a modified in-gel PTP activity assay was devised, as follows: As substrate, poly (4:1) Glu-Tyr (Sigma) was labeled with [γ-³²P]-ATP using the GST-FER fusion PTK, as described previously (Shen et al., 1998 J. Biol. Chem. 273:6474-81). The labeled substrates were used within three weeks to limit the variation of its specific activity from experiment to experiment. The lysis buffer (25 mM CH₃COONa, 1% NP-40, 150 mM NaCl, 10% glycerol, pH 5.5) was degassed at 4° C. for overnight, before catalase and superoxide dismutase (both 100 μg/ml), protease inhibitors and 10 mM iodoacetic acid (IAA) were added. Following stimulation, cells were lysed under anaerobic conditions in an argon chamber. Lysates (25 μg) were processed as described herein and an “in-gel” phosphatase assay (Burridge and Nelson, 1995) was conducted using SDS-PAGE gels containing a radioactively-labeled substrate (1.5×10⁶ cpm/20 ml gel solution, approximately 2 μM p-Tyr).

[0130] Cells were triggered with the appropriate stimulus and harvested under anaerobic conditions in lysis buffer containing IAA. Those PTPs that had not encountered ROS in the cell became irreversibly inactivated by alkylation of their active site Cys with IAA. However, in contrast, any PTPs in which the active site Cys had been oxidized in response to the stimulus were resistant to alkylation. For the “in-gel” phosphatase assay, a 10% SDS-PAGE gel was cast containing a radioactively-labeled substrate. An aliquot of cell lysate was subjected to SDS-PAGE and proteins in the gel were sequentially denatured, then renatured in the presence of reducing reagents. Under these conditions, the activity of the PTPs in which the active site Cys had been subjected to stimulus-dependent oxidation to sulfenic acid was recovered, whereas those that were not oxidized in response to the initial stimulus, and were irreversibly alkylated in the lysis step, remained inactive. The reaction was then terminated by fixing, staining and destaining the gel. Finally the gel was dried and exposed to film. The presence of a PTP was visualized by substrate dephosphorylation, as the appearance of a clear, white area on the black background of labeled substrate. As shown in FIG. 1, the PTPs that exhibited catalytic phosphatase activity in this assay would be those originally protected from post-lysis alkylation by a stimulus-dependent modification at the active site Cys, which was reversed by DTT, consistent with oxidation of the Cys to sulfenic acid.

[0131] The data shown in FIG. 2A illustrate that iodoacetic acid (IAA) in the lysis buffer effectively inactivated PTPs in a lysate of Rat-1 cells (lane 2, compared to lane 1), via irreversible alkylation of the invariant, active site Cys residue of these enzymes (Zhang and Dixon, 1993 Biochemistry 32:9340-45). FIG. 2A shows the results when serum-deprived Rat-1 cells were exposed to various concentrations of H₂O₂ for 1 min, harvested and lysed in the absence (lane 1) or presence (lanes 2-7) of 10 mM IAA. Aliquots of lysate were subjected to the in-gel PTP assay. When H₂O₂ was added to the culture media, it gained rapid access to the intracellular environment and within 1 minute the active site Cys residue of various PTPs was oxidized, thereby protecting them from alkylation by IAA (lanes 3-7, FIG. 2A). Furthermore, 200 μM H₂O₂ was sufficient to oxidize all of the PTPs detectable in this assay format, but more extensive oxidation occurred at higher concentrations of H₂O₂ (FIG. 2A).

[0132]FIG. 2B shows results obtained when tyrosine phosphorylated proteins were immunoprecipitated from lysates of H₂O₂-treated cells with Ab PT-66, then immunoblotted with anti-pTyr Ab (G104). The tyrosine phosphorylation of proteins of 120 kDa and 70 kDa was induced in a dose-dependent fashion coincident with exposure of cells to H₂O₂ (FIG. 2B), suggesting a link between oxidation/inhibition of PTPs and enhanced tyrosine phosphorylation in Rat-1 cells. This stimulation also triggered the phosphorylation of ERK MAP kinases (MAPKs). N-acetyl cysteine (NAC), a widely used ROS scavenger, blocked PTP oxidation and inactivation induced by 200 μM H₂O₂, thus confirming that the effects on PTP activity shown in the in-gel assay were due to H₂O₂-induced intracellular oxidation (FIG. 2C). FIG. 2C depicts the results obtained when cells were preincubated in the absence or presence of 30 mM NAC for 40 minutes and excess NAC removed by two washes with fresh culture medium, after which the Rat-1 cells were exposed to 200 μM H₂O₂ and lysed in the presence of 10 mM IAA at the indicated times. Lysates were subjected to the in-gel PTP assay.

[0133] In addition, depletion of the cellular pool of glutathione (GSH) by exposure of the cells to L-buthionine-SR-sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase, markedly attenuated the recovery of PTP activity following removal of an H₂O₂ stimulus (FIG. 2D). To obtain the data presented in FIG. 2D, Rat-1 cells were serum-starved in the absence or presence of 2.5 mM BSO for 16 h. H₂O₂ (200 μM) was added for 2 minutes, then removed by washing the cells with fresh culture media. Incubation was then continued until harvesting in lysis buffer containing 10 mM IAA at the times indicated. Oxidized PTPs were visualized by the in-gel phosphatase activity assay. Arrows indicate PTPs for which reduction/reactivation exhibited dependence on intracellular GSH. Stimulation with H₂O₂ led to oxidation of several PTPs (lane 2), which were quickly reduced once H₂O₂ was removed (FIG. 2D, lanes 3-6). Recovery was essentially complete within 10-20 minutes of removal of H₂O₂. However, when the same analysis was performed on Rat-1 cells that had been subjected to pretreatment with BSO, oxidation persisted even 30 minutes after removal of H₂O₂ (FIG. 2D lanes 8-12). Surprisingly, these observations provide the first demonstration that multiple PTPs may be oxidized and inactivated by ROS in a cellular environment.

Example 2 H₂O₂-Induced Mitogenic Signaling Associated with PTP Inactivation

[0134] In order to explore the importance of oxidation and inhibition of PTP function for ROS-induced mitogenesis, the effects of H₂O₂ and the synthetic ROS t-butyl hydroperoxide (t-BHP) were tested. Initially, the susceptibility of an activated mutant form of SHP-2 (E76A) to alkylation by IAA was compared following treatment with either H₂O₂ or t-BHP. Using the modified in-gel PTP assay described in Example 1, SHP-2, which had been pre-treated with PBS, was inactivated by IAA (lane 2, compared to lane 1, FIG. 3A), whereas oxidation with H₂O₂ protected SHP-2 from alkylation (FIG. 3A). Briefly, purified SHP-2 (E76A mutant) was incubated with PBS, H₂O₂ or t-BHP at 37° C. for 5 mins. Aliquots were then incubated at room temp for a further 5 minutes, either in the absence (−IAA) or presence (+IAA) of 4 mM IAA, and subjected to the in-gel PTP activity assay (1 ng SHP-2/lane). Even at 2 mM H₂O₂, SHP-2 was not irreversibly oxidized since its activity was recovered in the in-gel assay (FIG. 3A). In contrast, t-BHP was unable to oxidize and inactivate SHP-2 in vitro and thus did not protect the invariant Cys residue of SHP-2 from alkylation (FIG. 3A).

[0135] The effects of H₂O₂ and t-BHP on inactivation of PTPs and activation of MAPK signaling pathways were next compared in a cellular context. Intracellular ROS were measured using 2′,7′-dichlorofluorescein diacetate (H₂DCFDA) and 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H₂DCFDA) (all fluorescent ROS indicators from Molecular Probes, Eugene, Oreg.) either by fluorescence microscopy, using a Zeiss Axiovert 405M inverted microscope equipped with a fluorescence attachment and digital camera, or by cell sorting, using a FACSCalibur System (Coulter Instruments, Hialeah, Fla.), according to the manufacturer's recommendations. Rat-1 cells were pre-loaded with 20 μM H₂DCFDA in the dark for 20 mins, then exposed to H₂O₂ and t-BHP (both 200 μM) for 5 mins. Images of ROS-induced DCF fluorescence are shown at magnification 400× (FIG. 3B upper panel). Cells (1×10⁵) that underwent the same treatment as above were harvested and resuspended in Hanks' solution, then immediately subjected to flow cytometric analysis to measure ROS-induced DCF fluorescence. The basal peak indicates background fluorescence, whereas the rightward shifted peak indicates ROS-induced DCF fluorescence (FIG. 3B, lower panels). Initially, fluorescence microscopy of Rat-1 cells, preloaded with H₂DCFDA, showed that treatment with either H₂O₂ or t-BHP led to rapid oxidation and the appearance of the fluorescent derivative, DCF (upper panels, FIG. 3B). Furthermore, upon flow cytometric analysis no quantitative difference was observed between the H₂O₂- and t-BHP-induced shift of fluorescence (FIG. 3B, lower panels). However, when the ability to oxidize PTPs in the cells was examined, reproducible inactivation of PTPs was detected in response to H₂O₂ but not in response to t-BHP (FIG. 3C). Cells were exposed to H₂O₂ and t-BHP (each at 200 μM) for the indicated times, lysed in the presence of 10 mM IAA and oxidized PTPs were visualized in the in-gel PTP activity assay.

[0136] H₂O₂ and t-BHP were next compared for their effects on tyrosine phosphorylation of cellular proteins, and on activation of MAPKs. As shown in FIG. 3D, after exposure to H₂O₂ and t-BHP (each at 200 μM), lysates were prepared and pTyr proteins were immunoprecipitated with Ab PT-66, then immunoblotted with anti-pTyr Ab G104 (FIG. 3D, upper panel). An aliquot of lysate from each treatment group was immunoblotted with anti-phospho-MAPK Ab and subsequently with anti-MAPK Ab (FIG. 3D, lower panel). As shown in FIG. 3D, the inactivation of PTPs by H₂O₂ was associated with enhanced tyrosine phosphorylation and mitogenic signaling. In contrast, t-BHP elicited less pronounced effects on tyrosine phosphorylation and was unable to activate MAPKs (FIG. 3D), presumably due to its inability to oxidize and inactivate the PTPs. Without wishing to be bound by theory, these results are consistent with a role of PTP inactivation in the mitogenic effects of ROS.

Example 3 Oxidation of a 70 kDa PTP Associated with PDGF-Induced Mitogenic Signaling in Rat-1 Cells and Identification of the 70 kDa PTP as SHP-2

[0137] As described above, treatment of Rat-1 cells with H₂O₂ led to inactivation of multiple PTPs (FIGS. 2-3). This Example describes studies to determine whether the production of ROS in response to physiological stimuli also resulted in oxidation and inactivation of members of the PTP family, and whether there was specificity in the response. Initially examined were the effects of PDGF, a peptide growth factor, which has been shown to produce ROS in various cell types (Bae et al., 2000; Sundaresan et al., 1995). Preliminary experiments showed that treatment of Rat-1 cells with PDGF resulted in a rapid increase in the tyrosine phosphorylation of cellular proteins and the enhanced phosphorylation of MAPKs. Lysates of PDGF-stimulated Rat-1 cells were then analyzed using the modified in-gel PTP activity assay described above. The results, as shown in FIG. 4, demonstrated that PDGF stimulation induced a rapid and transient oxidation of a PTP having an apparent molecular mass of ˜70 kDa. Serum-starved Rat-1 cells were exposed to 50 ng/ml PDGF-BB for the times indicated (FIG. 4A). Lysates were prepared in the presence of 10 mM IAA and subjected to the in-gel PTP assay. The arrow indicates a 70 k PTP that was transiently oxidized following stimulation of Rat-1 cells with PDGF. The result shown is representative of four independent experiments. Oxidation of this 70 kDa PTP was reversible, reaching a maximum at 5 minutes, followed by marked reduction, almost to basal levels, within 20 minutes of PDGF treatment (FIG. 4A).

[0138] A possible role of oxidation/inactivation of the 70 k PTP in regulating PDGFR-mediated signaling was next investigated by testing the effects of the antioxidant NAC. Cells were incubated for 40 minutes in the presence or absence of 30 mM NAC prior to PDGF stimulation. Excess NAC was removed prior to addition of PDGF (50 ng/ml). PDGF-induced oxidation of the 70 k PTP, which was impaired in the presence of NAC (FIG. 4B, arrow), was visualized by the modified in-gel PTP assay. Then the modified in-gel PTP assay was used to examine the effects of the growth factor on the activity of the 70 k PTP. When the levels of PDGF-induced ROS were reduced by pretreatment with NAC, oxidation of the 70 k PTP was markedly attenuated (FIG. 4B). Furthermore, the ligand-induced tyrosine phosphorylation of the PDGFR was greatly diminished, and the activation of MAPKs was completely eliminated, in NAC-treated cells (FIG. 4C). Cells were treated with NAC and PDGF as described above. PDGFR was immunoprecipitated from lysates with Ab-X and immunoblotted with anti-pTyr Ab G104. The same filter was subsequently re-probed with Ab-X (FIG. 4C, upper panels). Aliquots of cell lysate from each treatment were immunoblotted with anti-phosho-MAPK Ab and re-probed with anti-MAPK Ab (FIG. 4C, lower panels). These data suggest that the rapid, transient inactivation of 70 k PTP may be important for concomitant PDGFR-mediated phosphorylation and mitogenic signaling.

[0139] In attempting to identify the 70 k PTP that was oxidized following PDGF stimulation, attention was drawn to the SH2 domain-containing PTP, SHP-2. This PTP has been shown to be associated with tyrosine phosphorylated PDGFR (Lechleider et al., 1993 J Biol. Chem. 268:21478-81). In addition, the apparent molecular weight of SHP-2 on SDS-PAGE is similar to that of the PDGF-responsive 70 k PTP detected in FIG. 4. Initially, it was confirmed that SHP-2 could be recruited by the ligand-activated PDGFR in Rat-1 cells. Serum-starved Rat-1 cells were exposed to PDGF (50 ng/ml) for the indicated times (FIG. 5A). The PDGFR and associated proteins were immunoprecipitated with antibody Ab-X, and pTyr proteins visualized by immunoblotting with anti-pTyr Ab G104 (FIG. 5A, upper panel). The same filter was re-probed with anti-PDGFR, anti-SHP-2, anti-GAP and anti-p85 P13K Abs. The positions of PDGFR (FIG. 5A, solid arrow) and SHP-2 (FIG. 5A, open arrow) are indicated. As shown in FIG. 5A (upper panel), a tyrosine phosphorylated protein of 70 kDa by SDS-PAGE associated rapidly with the PDGFR in response to ligand activation. Furthermore, immunoblotting was used to show that SHP-2 comigrated with this 70 k phosphoprotein (FIG. 5A, lower panels). The complex between PDGFR and SHP-2 persisted for up to 20 minutes after stimulation, then the level of association decreased (FIG. 5A, lower panels).

[0140] To test whether SHP-2 was the 70 k PTP that was oxidized following PDGF stimulation, SHP-2 protein was immunodepleted from cell lysates with increasing amounts of anti-SHP-2 antibody, and the supernatants were subjected to the modified in-gel PTP assay. Rat-1 cells, either untreated (−) or stimulated with 50 ng/ml PDGF (+), were harvested in lysis buffer containing 10 mM IAA. Lysates were incubated with antibody to either SHP-2 or SHP-1 and subjected to an in-gel PTP assay (FIG. 5B, upper panel). The arrow denotes the position of the 70 k PTP that was inactivated in response to PDGF and immunodepleted from cell lysates with antibodies to SHP-2. The lower panel of FIG. 5B illustrates an immunoblot to show the immunodepletion of SHP-2. As shown in FIG. 5B, anti-SHP-2 antibody depleted the 70 k PTP from Rat-1 cell lysates, whereas an anti-SHP-1 antibody control did not. These data identify SHP-2 as a PTP that was rapidly oxidized and inactivated following PDGF stimulation.

[0141] Association of other SH2 domain-containing proteins with activated PDGFR was also examined. It has been shown that SHP-2 dephosphorylates the PDGFR on the autophosphorylation sites that function as binding sites for GTPase-activating protein (GAP) and phosphatidylinositol 3 kinase (P13K) (Klinghoffer and Kazlauskas, 1995 J. Biol. Chem. 270:22208-17) (see also Kazlauskas et al., 1992 Mol. Cell Biol. 12:2534-44). However, both GAP and the p85 subunit of P13K were recruited by PDGFR rapidly after ligand stimulation, even though SHP-2 was associated with the receptor at this time (FIG. 5A). These results suggest that oxidation and inactivation of SHP-2 in response to PDGF may be important for permitting recruitment of GAP and P13K by the activated PDGFR. Interestingly, GAP and P13K dissociated from the receptor by 10 minutes after PDGF stimulation (FIG. 5A), coincident with dephosphorylation of PDGFRβ (FIG. 5A) and reactivation of SHP-2 (FIG. 4A).

Example 4 Specificity of ROS Production and SHP-2 Oxidation and Inactivation in Response to Growth Factor Stimulation

[0142] SHP-2 was one of the first PTPs to be recognized as capable of both negative signaling (by antagonizing PTK function) and positive signaling following a PTP-mediated dephosphorylation event, playing such a role, for example, in the context of EGF and FGF receptor signaling (Bennett et al., 1996 Mol. Biol. Cell 16:1189-1202; Saxton et al., 1997 EMBO J. 16:2352-64). The data described above, showing oxidation and inhibition of SHP-2 in response to PDGF, appear to be indicative of a negative role in signaling. This example describes additional characterization of a PTP response to a stimulus that induces a biological signaling pathway.

[0143] Treatment of Rat-1 cells with PDGF triggered production of intracellular ROS (FIG. 6A), concomitant with oxidation and inactivation of SHP-2 (FIG. 6B). In contrast, ROS production was not detected in response to either EGF or FGF (FIG. 6A). Rat-1 cells were incubated with 20 μM CM-H₂DCFDA in the dark for 20 mins, then exposed to peptide growth factors (50 ng/ml) for an additional 10 mins. Images of ROS-induced DCF fluorescence are shown at 50× magnification. (FIG. 6A) The data are representative of 4 independent experiments. In FIG. 6B, Rat-1 cells were exposed to peptide growth factors for the indicated times, lysed in the presence of 10 mM IAA, and oxidized PTPs were visualized by the in-gel PTP assay. In this assay, too, oxidation and inhibition of SHP-2 was observed following PDGF stimulation of the cells but not following exposure of these cells to EGF or FGF. EGF, FGF and PDGF all activated MAPK to a similar extent in Rat-1 cells (FIG. 6C). Aliquots of cell lysate from each treatment group were immunoblotted with anti-phospho-MAPK Ab and re-probed with anti-MAPK Ab. These results indicate that, of the stimuli examined in Rat-1 cells, transient oxidation and inactivation of SHP-2 is a specific response to PDGF, consistent with differences in the function of SHP-2 in these distinct growth factor signaling pathways.

[0144] The next set of experiments demonstrated that the PDGFR-associated pool of SHP-2 was susceptible to oxidation and inactivation. Recent studies have suggested that a Rac1-associated, plasma membrane-bound NADPH oxidase is responsible for PDGF-induced generation of ROS in non-phagocytic cells (Bae et al., 2000). In light of the short half-life of such ROS, it is possible that their influence on PTPs may be spatially restricted to the subcellular regions proximal to their production.

[0145] In preliminary studies only ˜10% of the total population of SHP-2 was recruited into a complex with the PDGFR following ligand stimulation in Rat-1 cells. To examine whether this recruitment was required for oxidation and inactivation of SHP-2 in response to PDGF, mutant forms of the PDGFR were constructed that were deficient in their association with SHP-2. Chimeric cell surface signal transduction receptors were also constructed which consisted of the extracellular segment of human granulocyte colony stimulating factor (G-CSF) receptor and the transmembrane and cytoplasmic segments of human PDGFR. The ability of these mutant PDGFRs to induce oxidation of the PTP in response to ligand was then tested.

[0146] Full length cDNA encoding wild type (WT) and Y1009F mutant forms of human PDGFRβ was provided by Dr. Jonathan Cooper (Fred Hutchinson Cancer Center, Seattle, Wash.; (Kashishian and Cooper, 1993 Mol. Biol. Cell 4:49-57)). The cDNA encoding the extracellular segment of human G-CSFR was a gift from Dr. Shigekazu Nagata (Osaka University, Japan; (Fukada et al., 1996)). Chimeric receptors comprising the extracellular segment of G-CSFR fused to the transmembrane and intracellular (WT and Y1009F) segments of PDGFRβ were constructed in the pcDNA3.1A vector (Invitrogen) by standard PCR protocols then inserted into a pRK5 expression vector for transient transfection experiments. The integrity of the constructs was confirmed by sequencing. These chimeric receptors permitted examination of G-CSF-induced recruitment of SHP-2 to the chimeric receptors and signaling in Rat-1 cells, which do not express endogenous G-CSF receptor (G-CSFR), while avoiding activation of endogenous PDGFR. The autophosphorylation site at Y 1009 of human PDGFR has been shown to be the major docking site for the N-terminal SH2 domain of SHP-2 (Lechleider et al., 1993).

[0147] Expression constructs encoding chimeric receptors comprising either wild type (WT) or Y1009F forms of the PDGFR intracellular segment were transiently transfected into Rat-1 cells. Upon stimulation with G-CSF, both WT and Y1009F chimeric receptors were tyrosine phosphorylated (FIG. 7A). Although both receptors were activated following treatment with G-CSF, only the WT recruited SHP-2, which was recovered in immune-complexes precipitated with antibodies to the intracellular segment of the PDGFR (FIG. 7A). Using the modified in-gel PTP assay, WT chimeric receptors triggered rapid oxidation and inactivation of SHP-2 in response to G-CSF stimulation. Rat-1 cells were transiently transfected with plasmids expressing WT or Y1009F mutant G-CSFR/PDGFR chimeric receptor, or with a plasmid encoding Green Fluorescence Protein (GFP) as a control for expression. After exposure to 100 ng/ml G-CSF for 5 min, the chimeric receptors were immunoprecipiated from lysates with antibody Ab-X and immunoblotted with anti-pTyr Ab G104. (FIG. 7A) Immunoprecipitation of the receptors was verified by immunoblotting with Ab-X. The same filter was stripped and reprobed with anti-SHP-2 Ab. Expression of the chimeric receptors was verified by immunoblotting an aliquot of each lysate with Ab-X, which recognizes the intracellular segment of the PDGFR, and subsequently with anti-G-CSFR Ab, which recognizes the extracellular segment of chimeric receptors, as also shown in FIG. 7A.

[0148] Next, transfected Rat-1 cells were treated with G-CSF for the indicated times, lysed in the presence of 10 mM IAA and the lysates subjected to an in-gel PTP assay. (FIG. 7B) Activation of Y1009F mutant receptors did not induce oxidation of SHP-2 (FIG. 7B), suggesting according to non-limiting theory that recruitment of SHP-2 by activated, chimeric PDGFR was required for oxidation of the PTP by ROS generated in response to ligand. The arrow denotes the position of SHP-2.

[0149] Using the G-CSF:PDGF receptor chimeras, a time course of exposure to G-CSF illustrated that both WT and Y1009F, SHP-2 docking site mutant receptors were rapidly tyrosine phosphorylated following ligand stimulation. However, whereas tyrosine phosphorylation of the WT receptor was transient, the mutant receptor was maintained at a higher level of phosphorylation throughout the time course (FIG. 7C). The differences were particularly striking at the later time points, following 20 and 30 minutes of ligand stimulation. As shown in FIG. 7C, the WT and mutant chimeric receptors were immunoprecipitated at the indicated times and immunoblotted with anti-pTyr Ab (G104). The same filter was re-probed with anti-PDGFR Ab-X.

[0150] The phosphorylation status of MAPKs in the cell lysates was also investigated by immunoblotting analysis with antibodies specific for the phosphorylated and dephosphorylated forms of MAPK. Maximal phosphorylation of p42 and p44 ERKs following 20 minutes of stimulation (FIG. 7D). FIG. 7D shows the results obtained when aliquots of lysate from each treatment group were also subjected to immunoblotting with anti-phosho-MAPK Ab, and then re-probed with anti-MAPK Ab. However, both the extent and duration of ERK phosphorylation was higher in cells expressing the mutant receptor, which was deficient in binding of SHP-2, compared to those expressing the wild type receptor (FIGS. 7D & E). As shown in FIG. 7E, densitometric analysis of the gel image of FIG. 7D illustrates the ratio of phosphorylated (upper panel of 7D) over total (lower panel of 7D) MAPK. Without wishing to be bound by theory, these results suggest that recruitment of SHP-2 into the PDGF receptor-containing signaling complex is important for down-regulation of both receptor tyrosine phosphorylation and activation of MAPK, and that oxidation and inhibition of SHP-2 in the early phase of the response to PDGF is important for establishment of the signaling response.

Example 5 Prior Treatment of Cells with a PTP Active Site-Binding Agent Protects Against IAA-Mediated PTP Inactivation

[0151] An in-gel protection assay was developed to show that a small molecule PTP inhibitor could bind to the active site of the PTP and protect the active site cysteine from alkylation or from other irreversible modifications. An independently developed PTP inhibitor was shown to inhibit PTP catalytic activity and characterized by X-ray crystallography as a PTP active site-binding agent. This PTP inhibitor, referred to here as ASBA-1, was used to demonstrate that the PTP inhibitor could specifically bind to a PTP in an activated blood cell.

[0152] Peripheral blood mononuclear lymphocytes were purified from human blood. In 5 ml media (RPMI), 2×10⁷ cells were incubated in 50 μM ASBA-1 (PTP specific inhibitor) for 90 minutes and stimulated with phytohemagglutinin (PHA, 0.5 μL of 5.0 mg/ml stock) for 2, 10 or 30 min. Cells were pelleted, washed and lysed in buffer in the presence or absence of 50 mM iodoacetic acid (IAA) in extraction buffer (50 mM Tris, pH 7.5; 1 mM EDTA; 1 mM EGTA; 0.25% Triton X-100; 1 ug/mL pepstatin, aprotinin, and leupeptin; 1 mM benzamidine). Desalted proteins were separated on a 2 ml Source Q anion exchange column (Amersham Pharmacia Biotech) using a 0-1M NaCl gradient in 20 mM Tris, pH 7.5; 1 mM EDTA; 0.05% Triton X-100. Samples of each fraction were analyzed by the in-gel PTP assay (described above) and the results are shown in FIG. 9. At least two IAA-insensitive, PTP activity bands were observed from ASBA-1-treated cells, following autoradiography of the dried gel (FIG. 9, left panel). In samples from cells in which these proteins were not protected by ASBA-1 pretreatment, the PTPs were inactivated by IAA and PTP activity was not observed in the corresponding gel region using the in-gel PTP activity assay (FIG. 9, right panel). Therefore, and according to non-limiting theory, specific binding of ASBA-1 to the active sites of at least two PTPs in these cells prevented complete inactivation of the PTPs by IAA.

Example 6 Insulin Signaling Mediated by ROS Production

[0153] The role of intracellular production of ROS (e.g., H₂O₂) in insulin-mediated signal transduction was examined. Rat-1 fibroblasts were cultured and then serum starved for 16 hours as described in Example 1. The cells were preloaded with 5 μM CM-H₂DCFDA (Molecular Probes, Eugene, Oreg., Cat. No. D-399) in the dark for 15 min and then exposed to 50 nM insulin for 10 minutes. Images of ROS-induced DCF fluorescence were captured by fluorescence microscopy using a Zeiss Axiovert 405M inverted microscope equipped with a fluorescence attachment and digital camera (see Example 2), and are shown at 50× magnification in FIG. 10A.

[0154] Ectopic expression of catalase, which suppresses intracellular H₂O₂ production, impaired both tyrosine phosphorylation of the β-subunit of the insulin receptor (IR-β) and the phosphorylation of the downstream signaling molecule PKB/Akt in response to insulin stimulation. Rat-1 cells were transiently transfected as described in Example 1 with different quantities of plasmid encoding human catalase (a gift from Dr. Toren Finkle, NIH, Bethesda Md.) or with empty vector. Two days after transfection, cells were serum-deprived, then stimulated with 50 nM insulin (INS) for 10 min. The cells were lysed in 20 mM Hepes (pH 7.5), 1% NP-40, 150 mM NaCl, 10% glycerol, and 200 μM Na₃VO₄ containing 25 μg/ml each of aprotinin and leupeptin. Immunoblotting and immunoprecipitation were then performed essentially as described in Example 1. Catalase expression was verified by immunoblotting with an anti-catalase antibody (Calbiochem®, San Diego, Calif.) as shown in FIG. 10B (top panel). The IR-β subunit was immunoprecipitated from 400 μg of the cell lysate with antibody 29B4 (Santa Cruz). The lysate was separated by SDS-PAGE and then immunoblotted with anti-pYpY^(1162/1163) (Biosource International, Camarillo, Calif.) to examine the phosphorylation status of the receptor. The immunoblot was subsequently probed with anti-IR-β antibody clone C-19 (Santa Cruz) as a loading control (FIG. 10B, middle panel). An aliquot of lysate (30 μg) was subjected to immunoblotting with anti-phospho-PKB/AKT antibody (Cell Signaling). The same filter was then stripped and re-probed with anti-PKB/AKT antibody (Cell Signaling) as a loading control (FIG. 10B, bottom panel).

Example 7 Insulin Induces Transient Oxidation of PTP1B and TC45

[0155] The effect of insulin-induced H₂O₂ production on PTP oxidation was examined using the modified in-gel PTP assay essentially as described in Example 1. Serum-starved Rat-1 cells were exposed to 50 nM insulin for 2, 5, 10, 20, and 30 minutes. Lysates were prepared under anaerobic conditions in the presence of 10 mM IAA and then subjected to in-gel PTP assays. The substrate incorporated into the SDS-PAGE gels for these assays was ³²P-labeled reduced, carboxamidomethylated and maleylated lysozyme (RCML) (1.5×10⁶ cpm/20 ml gel solution, ˜2 μM p-Tyr). FIG. 11A shows that a PTP having an approximate molecular weight of 50 kDa and a PTP with an approximate molecular weight of 45 kDa were transiently oxidized in response to insulin.

[0156] The oxidized 45 kDa and 50 kDa PTPs were identified as TC-45 and PTP1B, respectively, by immunodepletion and immunoblotting. Total cell lysates were prepared as described in Example 1. Lysate (400 μg) was incubated with normal IgG, anti-PTP1B antibody (FG6, LaMontagne et al., Mol. Cell. Biol. 18:2965-75 (1998)), or anti-TC45 antibody (1910H, Lorenzen et al., J. Cell. Biol. 131:631-43 (1995)) coupled to protein G-Sepharose ^(T) beads (Amersham Biosciences). After the immunoprecipitation step, the immune complexes and supernatants were collected and subjected to in-gel PTP assays. Immunodepletion of the 50 kDa PTP from the lysate with anti-PTP1B antibody is shown in FIG. 11B, and immunodepletion of the 45 kDa PTP with antibody specific for TC45 is shown in FIG. 11C. Cell lysate prior to immunodepletion is represented in the lane marked “Lys” in FIGS. 11B and 11C. Total cell lysate and supernatants were separated by SDS-PAGE, transferred to nitrocellulose membranes, and immunoblotted with either anti-PTP1B antibody (FIG. 11B) or anti-TC45 antibody (FIG. 11C). The immunoblots show that each PTP protein is depleted after immunoprecipitation with the specific antibody. The same immunoblots were subsequently reprobed with anti-SHP-2 antibody to illustrate that comparable amounts of polypeptide were loaded onto each gel.

[0157] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 98 <210> SEQ ID NO 1 <211> LENGTH: 3247 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 gggcgggcct cggggctaag agcgcgacgc ctagagcggc agacggcgca gtgggccgag 60 aaggaggcgc agcagccgcc ctggcccgtc atggagatgg aaaaggagtt cgagcagatc 120 gacaagtccg ggagctgggc ggccatttac caggatatcc gacatgaagc cagtgacttc 180 ccatgtagag tggccaagct tcctaagaac aaaaaccgaa ataggtacag agacgtcagt 240 ccctttgacc atagtcggat taaactacat caagaagata atgactatat caacgctagt 300 ttgataaaaa tggaagaagc ccaaaggagt tacattctta cccagggccc tttgcctaac 360 acatgcggtc acttttggga gatggtgtgg gagcagaaaa gcaggggtgt cgtcatgctc 420 aacagagtga tggagaaagg ttcgttaaaa tgcgcacaat actggccaca aaaagaagaa 480 aaagagatga tctttgaaga cacaaatttg aaattaacat tgatctctga agatatcaag 540 tcatattata cagtgcgaca gctagaattg gaaaacctta caacccaaga aactcgagag 600 atcttacatt tccactatac cacatggcct gactttggag tccctgaatc accagcctca 660 ttcttgaact ttcttttcaa agtccgagag tcagggtcac tcagcccgga gcacgggccc 720 gttgtggtgc 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ttttactttt tgccccttcc actttgagta ccaaatccac 1620 aagccatttt ttgaggagag tgaaagagag taccatgctg gcggcgcaga gggaaggggc 1680 ctacacccgt cttggggctc gccccaccca gggctccctc ctggagcatc ccaggcggcg 1740 cacgccaaca gcccccccct tgaatctgca gggagcaact ctccactcca tatttattta 1800 aacaattttt tccccaaagg catccatagt gcactagcat tttcttgaac caataatgta 1860 ttaaaatttt ttgatgtcag ccttgcatca agggctttat caaaaagtac aataataaat 1920 cctcaggtag tactgggaat ggaaggcttt gccatgggcc tgctgcgtca gaccagtact 1980 gggaaggagg acggttgtaa gcagttgtta tttagtgata ttgtgggtaa cgtgagaaga 2040 tagaacaatg ctataatata taatgaacac gtgggtattt aataagaaac atgatgtgag 2100 attactttgt cccgcttatt ctcctccctg ttatctgcta gatctagttc tcaatcactg 2160 ctcccccgtg tgtattagaa tgcatgtaag gtcttcttgt gtcctgatga aaaatatgtg 2220 cttgaaatga gaaactttga tctctgctta ctaatgtgcc ccatgtccaa gtccaacctg 2280 cctgtgcatg acctgatcat tacatggctg tggttcctaa gcctgttgct gaagtcattg 2340 tcgctcagca atagggtgca gttttccagg aataggcatt tgctaattcc tggcatgaca 2400 ctctagtgac ttcctggtga ggcccagcct gtcctggtac agcagggtct tgctgtaact 2460 cagacattcc aagggtatgg gaagccatat tcacacctca cgctctggac atgatttagg 2520 gaagcaggga caccccccgc cccccacctt tgggatcagc ctccgccatt ccaagtcaac 2580 actcttcttg agcagaccgt gatttggaag agaggcacct gctggaaacc acacttcttg 2640 aaacagcctg ggtgacggtc ctttaggcag cctgccgccg tctctgtccc ggttcacctt 2700 gccgagagag gcgcgtctgc cccaccctca aaccctgtgg ggcctgatgg tgctcacgac 2760 tcttcctgca aagggaactg aagacctcca cattaagtgg ctttttaaca tgaaaaacac 2820 ggcagctgta gctcccgagc tactctcttg ccagcatttt cacattttgc ctttctcgtg 2880 gtagaagcca gtacagagaa attctgtggt gggaacattc gaggtgtcac cctgcagagc 2940 tatggtgagg tgtggataag gcttaggtgc caggctgtaa gcattctgag ctggcttgtt 3000 gtttttaagt cctgtatatg tatgtagtag tttgggtgtg tatatatagt agcatttcaa 3060 aatggacgta ctggtttaac ctcctatcct tggagagcag ctggctctcc accttgttac 3120 acattatgtt agagaggtag cgagctgctc tgctatatgc cttaagccaa tatttactca 3180 tcaggtcatt attttttaca atggccatgg aataaaccat ttttacaaaa ataaaaacaa 3240 aaaaagc 3247 <210> SEQ ID NO 2 <211> LENGTH: 435 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Glu Met Glu Lys Glu Phe Glu Gln Ile Asp Lys Ser Gly Ser Trp 1 5 10 15 Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe Pro Cys 20 25 30 Arg Val Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr Arg Asp 35 40 45 Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu Asp Asn 50 55 60 Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln Arg Ser 65 70 75 80 Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His Phe Trp 85 90 95 Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu Asn Arg 100 105 110 Val Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro Gln Lys 115 120 125 Glu Glu Lys Glu Met Ile Phe Glu Asp Thr Asn Leu Lys Leu Thr Leu 130 135 140 Ile Ser Glu Asp Ile Lys Ser Tyr Tyr Thr Val Arg Gln Leu Glu Leu 145 150 155 160 Glu Asn Leu Thr Thr Gln Glu Thr Arg Glu Ile Leu His Phe His Tyr 165 170 175 Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe Leu 180 185 190 Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Pro Glu His 195 200 205 Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 210 215 220 Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg Lys Asp 225 230 235 240 Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg Lys Phe 245 250 255 Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser Tyr Leu 260 265 270 Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser Val Gln 275 280 285 Asp Gln Trp Lys Glu Leu Ser His Glu Asp Leu Glu Pro Pro Pro Glu 290 295 300 His Ile Pro Pro Pro Pro Arg Pro Pro Lys Arg Ile Leu Glu Pro His 305 310 315 320 Asn Gly Lys Cys Arg Glu Phe Phe Pro Asn His Gln Trp Val Lys Glu 325 330 335 Glu Thr Gln Glu Asp Lys Asp Cys Pro Ile Lys Glu Glu Lys Gly Ser 340 345 350 Pro Leu Asn Ala Ala Pro Tyr Gly Ile Glu Ser Met Ser Gln Asp Thr 355 360 365 Glu Val Arg Ser Arg Val Val Gly Gly Ser Leu Arg Gly Ala Gln Ala 370 375 380 Ala Ser Pro Ala Lys Gly Glu Pro Ser Leu Pro Glu Lys Asp Glu Asp 385 390 395 400 His Ala Leu Ser Tyr Trp Lys Pro Phe Leu Val Asn Met Cys Val Ala 405 410 415 Thr Val Leu Thr Ala Gly Ala Tyr Leu Cys Tyr Arg Phe Leu Phe Asn 420 425 430 Ser Asn Thr 435 <210> SEQ ID NO 3 <211> LENGTH: 3318 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 gtgatgcgta gttccggctg ccggttgaca tgaagaagca gcagcggcta gggcggcggt 60 agctgcaggg gtcggggatt gcagcgggcc tcggggctaa gagcgcgacg cggcctagag 120 cggcagacgg cgcagtgggc cgagaaggag gcgcagcagc cgccctggcc cgtcatggag 180 atggaaaagg agttcgagca gatcgacaag tccgggagct gggcggccat ttaccaggat 240 atccgacatg aagccagtga cttcccatgt agagtggcca agcttcctaa gaacaaaaac 300 cgaaataggt acagagacgt cagtcccttt gaccatagtc ggattaaact acatcaagaa 360 gataatgact atatcaacgc tagtttgata aaaatggaag aagcccaaag gagttacatt 420 cttacccagg gccctttgcc taacacatgc ggtcactttt gggagatggt gtgggagcag 480 aaaagcaggg gtgtcgtcat gctcaacaga gtgatggaga aaggttcgtt aaaatgcgca 540 caatactggc cacaaaaaga agaaaaagag atgatctttg aagacacaaa tttgaaatta 600 acattgatct ctgaagatat caagtcatat tatacagtgc gacagctaga attggaaaac 660 cttacaaccc aagaaactcg agagatctta catttccact ataccacatg gcctgacttt 720 ggagtccctg aatcaccagc ctcattcttg aactttcttt tcaaagtccg agagtcaggg 780 tcactcagcc cggagcacgg gcccgttgtg gtgcactgca gtgcaggcat cggcaggtct 840 ggaaccttct gtctggctga tacctgcctc ttgctgatgg acaagaggaa agacccttct 900 tccgttgata tcaagaaagt gctgttagaa atgaggaagt ttcggatggg gctgatccag 960 acagccgacc agctgcgctt ctcctacctg gctgtgatcg aaggtgccaa attcatcatg 1020 ggggactctt ccgtgcagga tcagtggaag gagctttccc acgaggacct ggagccccca 1080 cccgagcata tccccccacc tccccggcca cccaaacgaa tcctggagcc acacaatggg 1140 aaatgcaggg agttcttccc aaatcaccag tgggtgaagg aagagaccca ggaggataaa 1200 gactgcccca tcaaggaaga aaaaggaagc cccttaaatg ccgcacccta cggcatcgaa 1260 agcatgagtc aagacactga agttagaagt cgggtcgtgg ggggaagtct tcgaggtgcc 1320 caggctgcct ccccagccaa aggggagccg tcactgcccg agaaggacga ggaccatgca 1380 ctgagttact ggaagccctt cctggtcaac atgtgcgtgg ctacggtcct cacggccggc 1440 gcttacctct gctacaggtt cctgttcaac agcaacacat agcctgaccc tcctccactc 1500 cacctccacc cactgtccgc ctctgcccgc agagcccacg cccgactagc aggcatgccg 1560 cggtaggtaa gggccgccgg accgcgtaga gagccgggcc ccggacggac gttggttctg 1620 cactaaaacc catcttcccc ggatgtgtgt ctcacccctc atccttttac tttttgcccc 1680 ttccactttg agtaccaaat ccacaagcca ttttttgagg agagtgaaag agagtaccat 1740 gctggcggcg cagagggaag gggcctacac ccgtcttggg gctcgcccca cccagggctc 1800 cctcctggag catcccaggc gggcggcacg ccaacagccc cccccttgaa tctgcaggga 1860 gcaactctcc actccatatt tatttaaaca attttttccc caaaggcatc catagtgcac 1920 tagcattttc ttgaaccaat aatgtattaa aattttttga tgtcagcctt gcatcaaggg 1980 ctttatcaaa aagtacaata ataaatcctc aggtagtact gggaatggaa ggctttgcca 2040 tgggcctgct gcgtcagacc agtactggga aggaggacgg ttgtaagcag ttgttattta 2100 gtgatattgt gggtaacgtg agaagataga acaatgctat aatatataat gaacacgtgg 2160 gtatttaata agaaacatga tgtgagatta ctttgtcccg cttattctcc tccctgttat 2220 ctgctagatc tagttctcaa tcactgctcc cccgtgtgta ttagaatgca tgtaaggtct 2280 tcttgtgtcc tgatgaaaaa tatgtgcttg aaatgagaaa ctttgatctc tgcttactaa 2340 tgtgccccat gtccaagtcc aacctgcctg tgcatgacct gatcattaca tggctgtggt 2400 tcctaagcct gttgctgaag tcattgtcgc tcagcaatag ggtgcagttt tccaggaata 2460 ggcatttgcc taattcctgg catgacactc tagtgacttc ctggtgaggc ccagcctgtc 2520 ctggtacagc agggtcttgc tgtaactcag acattccaag ggtatgggaa gccatattca 2580 cacctcacgc tctggacatg atttagggaa gcagggacac cccccgcccc ccacctttgg 2640 gatcagcctc cgccattcca agtcaacact cttcttgagc agaccgtgat ttggaagaga 2700 ggcacctgct ggaaaccaca cttcttgaaa cagcctgggt gacggtcctt taggcagcct 2760 gccgccgtct ctgtcccggt tcaccttgcc gagagaggcg cgtctgcccc accctcaaac 2820 cctgtggggc ctgatggtgc tcacgactct tcctgcaaag ggaactgaag acctccacat 2880 taagtggctt tttaacatga aaaacacggc agctgtagct cccgagctac tctcttgcca 2940 gcattttcac attttgcctt tctcgtggta gaagccagta cagagaaatt ctgtggtggg 3000 aacattcgag gtgtcaccct gcagagctat ggtgaggtgt ggataaggct taggtgccag 3060 gctgtaagca ttctgagctg ggcttgttgt ttttaagtcc tgtatatgta tgtagtagtt 3120 tgggtgtgta tatatagtag catttcaaaa tggacgtact ggtttaacct cctatccttg 3180 gagagcagct ggctctccac cttgttacac attatgttag agaggtagcg agctgctctg 3240 ctatatgcct taagccaata tttactcatc aggtcattat tttttacaat ggccatggaa 3300 taaaccattt ttacaaaa 3318 <210> SEQ ID NO 4 <211> LENGTH: 435 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Glu Met Glu Lys Glu Phe Glu Gln Ile Asp Lys Ser Gly Ser Trp 1 5 10 15 Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe Pro Cys 20 25 30 Arg Val Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr Arg Asp 35 40 45 Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu Asp Asn 50 55 60 Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln Arg Ser 65 70 75 80 Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His Phe Trp 85 90 95 Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu Asn Arg 100 105 110 Val Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro Gln Lys 115 120 125 Glu Glu Lys Glu Met Ile Phe Glu Asp Thr Asn Leu Lys Leu Thr Leu 130 135 140 Ile Ser Glu Asp Ile Lys Ser Tyr Tyr Thr Val Arg Gln Leu Glu Leu 145 150 155 160 Glu Asn Leu Thr Thr Gln Glu Thr Arg Glu Ile Leu His Phe His Tyr 165 170 175 Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe Leu 180 185 190 Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Pro Glu His 195 200 205 Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 210 215 220 Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg Lys Asp 225 230 235 240 Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg Lys Phe 245 250 255 Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser Tyr Leu 260 265 270 Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser Val Gln 275 280 285 Asp Gln Trp Lys Glu Leu Ser His Glu Asp Leu Glu Pro Pro Pro Glu 290 295 300 His Ile Pro Pro Pro Pro Arg Pro Pro Lys Arg Ile Leu Glu Pro His 305 310 315 320 Asn Gly Lys Cys Arg Glu Phe Phe Pro Asn His Gln Trp Val Lys Glu 325 330 335 Glu Thr Gln Glu Asp Lys Asp Cys Pro Ile Lys Glu Glu Lys Gly Ser 340 345 350 Pro Leu Asn Ala Ala Pro Tyr Gly Ile Glu Ser Met Ser Gln Asp Thr 355 360 365 Glu Val Arg Ser Arg Val Val Gly Gly Ser Leu Arg Gly Ala Gln Ala 370 375 380 Ala Ser Pro Ala Lys Gly Glu Pro Ser Leu Pro Glu Lys Asp Glu Asp 385 390 395 400 His Ala Leu Ser Tyr Trp Lys Pro Phe Leu Val Asn Met Cys Val Ala 405 410 415 Thr Val Leu Thr Ala Gly Ala Tyr Leu Cys Tyr Arg Phe Leu Phe Asn 420 425 430 Ser Asn Thr 435 <210> SEQ ID NO 5 <211> LENGTH: 2346 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 5 gaattcggga tccttttgca cattcctagt tagcagtgca tactcatcag actggagatg 60 tttaatgaca tcagggaacc aaacggacaa cccatagtac ccgaagacag ggtgaaccag 120 acaatcgtaa gcttgatggt gttttccctg actgggtagt tgaagcatct catgaatgtc 180 agccaaattc cgtacagttc ggtgcggatc cgaacgaaac acctcctgta ccaggttccc 240 gtgtcgctct caatttcaat cagctcatct atttgtttgg gagtcttgat tttatttacc 300 gtgaagacct tctctggctg gccccgggct ctcatgttgg tgtcatgaat taacttcaga 360 atcatccagg cttcatcatg ttttcccacc tccagcaaga accgagggct ttctggcatg 420 aaggtgagag ccaccacaga ggagacgcat gggagcgcac agacgatgac gaagacgcgc 480 cacgtgtgga actggtaggc tgaacccatg ctgaagctcc acccgtagtg gggaatgatg 540 gcccaggcat ggcggaggct agatgccgcc aatcatccag aacatgcaga agccgctgct 600 ggggagcttg gggctgcggt ggtggcgggt gacgggcttc gggacgcgga gcgacgcggc 660 ctagcgcggc ggacggccgt gggaactcgg gcagccgacc cgtcccgcca tggagatgga 720 gaaggagttc gaggagatcg acaaggctgg gaactgggcg gctatttacc aggacattcg 780 acatgaagcc agcgacttcc catgcaaagt cgcgaagctt cctaagaaca aaaaccggaa 840 caggtaccga gatgtcagcc cttttgacca cagtcggatt aaattgcacc aggaagataa 900 tgactatatc aatgccagct tgataaaaat ggaagaagcc cagaggagct atattctcac 960 ccagggccct ttaccaaaca catgtgggca cttctgggag atggtgtggg agcagaagag 1020 caggggcgtg gtcatgctca accgcatcat ggagaaaggc tcgttaaaat gtgcccagta 1080 ttggccacag caagaagaaa aggagatggt ctttgatgac acaggtttga agttgacact 1140 aatctctgaa gatgtcaagt catattacac agtacgacag ttggagttgg aaaacctgac 1200 taccaaggag actcgagaga tcctgcattt ccactacacc acatggcctg actttggagt 1260 ccccgagtca ccggcttctt tcctcaattt ccttttcaaa gtccgagagt caggctcact 1320 cagcctggag catggcccca ttgtggtcca ctgcagcgcc ggcatcggga ggtcagggac 1380 cttctgtctg gctgacacct gcctcttact gatggacaag aggaaagacc catcttccgt 1440 ggacatcaag aaagtactgc tggagatgcg caggttccgc atggggctca tccagactgc 1500 cgaccagctg cgcttctcct acctggctgt catcgagggc gccaagttca tcatgggcga 1560 ctcgtcagtg caggatcagt ggaaggagct ctcccgggag gatctagacc ttccacccga 1620 gcacgtgccc ccacctcccc ggccacccaa acgcacactg gagcctcaca acgggaagtg 1680 caaggagctc ttctccagcc accagtgggt gagcgaggag acctgtgggg atgaagacag 1740 cctggccaga gaggaaggca gagcccagtc aagtgccatg cacagcgtga gcagcatgag 1800 tccagacact gaagttagga gacggatggt gggtggaggt cttcaaagtg ctcaggcgtc 1860 tgtccccacc gaggaagagc tgtcctccac tgaggaggaa cacaaggcac attggccaag 1920 tcactggaag cccttcctgg tcaatgtgtg catggccacg ctcctggcca ccggcgcgta 1980 cttgtgctac cgggtgtgtt ttcactgaca gactgggagg cactgccact gcccagctta 2040 ggatgcggtc tgcggcgtct gacctggtgt agagggaaca acaactcgca agcctgctct 2100 ggaactggaa gggcctgccc caggagggta ttagtgcact gggctttgaa ggagcccctg 2160 gtcccacgaa cagagtctaa tctcagggcc ttaacctgtt caggagaagt agaggaaatg 2220 ccaaatactc ttcttgctct cacctcactc ctcccctttc tctgattcat ttgtttttgg 2280 aaaaaaaaaa aaaaagaatt acaacacatt gttgttttta acatttataa aggcaggccc 2340 gaattc 2346 <210> SEQ ID NO 6 <211> LENGTH: 432 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 6 Met Glu Met Glu Lys Glu Phe Glu Glu Ile Asp Lys Ala Gly Asn Trp 1 5 10 15 Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe Pro Cys 20 25 30 Lys Val Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr Arg Asp 35 40 45 Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu Asp Asn 50 55 60 Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln Arg Ser 65 70 75 80 Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His Phe Trp 85 90 95 Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu Asn Arg 100 105 110 Ile Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro Gln Gln 115 120 125 Glu Glu Lys Glu Met Val Phe Asp Asp Thr Gly Leu Lys Leu Thr Leu 130 135 140 Ile Ser Glu Asp Val Lys Ser Tyr Tyr Thr Val Arg Gln Leu Glu Leu 145 150 155 160 Glu Asn Leu Thr Thr Lys Glu Thr Arg Glu Ile Leu His Phe His Tyr 165 170 175 Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe Leu 180 185 190 Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Leu Glu His 195 200 205 Gly Pro Ile Val Val His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 210 215 220 Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg Lys Asp 225 230 235 240 Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg Arg Phe 245 250 255 Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser Tyr Leu 260 265 270 Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser Val Gln 275 280 285 Asp Gln Trp Lys Glu Leu Ser Arg Glu Asp Leu Asp Leu Pro Pro Glu 290 295 300 His Val Pro Pro Pro Pro Arg Pro Pro Lys Arg Thr Leu Glu Pro His 305 310 315 320 Asn Gly Lys Cys Lys Glu Leu Phe Ser Ser His Gln Trp Val Ser Glu 325 330 335 Glu Thr Cys Gly Asp Glu Asp Ser Leu Ala Arg Glu Glu Gly Arg Ala 340 345 350 Gln Ser Ser Ala Met His Ser Val Ser Ser Met Ser Pro Asp Thr Glu 355 360 365 Val Arg Arg Arg Met Val Gly Gly Gly Leu Gln Ser Ala Gln Ala Ser 370 375 380 Val Pro Thr Glu Glu Glu Leu Ser Ser Thr Glu Glu Glu His Lys Ala 385 390 395 400 His Trp Pro Ser His Trp Lys Pro Phe Leu Val Asn Val Cys Met Ala 405 410 415 Thr Leu Leu Ala Thr Gly Ala Tyr Leu Cys Tyr Arg Val Cys Phe His 420 425 430 <210> SEQ ID NO 7 <211> LENGTH: 3247 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 gggcgggcct cggggctaag agcgcgacgc ctagagcggc agacggcgca gtgggccgag 60 aaggaggcgc agcagccgcc ctggcccgtc atggagatgg aaaaggagtt cgagcagatc 120 gacaagtccg ggagctgggc ggccatttac caggatatcc gacatgaagc cagtgacttc 180 ccatgtagag tggccaagct tcctaagaac aaaaaccgaa ataggtacag agacgtcagt 240 ccctttgacc atagtcggat taaactacat caagaagata atgactatat caacgctagt 300 ttgataaaaa tggaagaagc ccaaaggagt tacattctta cccagggccc tttgcctaac 360 acatgcggtc acttttggga gatggtgtgg gagcagaaaa gcaggggtgt cgtcatgctc 420 aacagagtga tggagaaagg ttcgttaaaa tgcgcacaat actggccaca aaaagaagaa 480 aaagagatga tctttgaaga cacaaatttg aaattaacat tgatctctga agatatcaag 540 tcatattata cagtgcgaca gctagaattg gaaaacctta caacccaaga aactcgagag 600 atcttacatt tccactatac cacatggcct gactttggag tccctgaatc accagcctca 660 ttcttgaact ttcttttcaa agtccgagag tcagggtcac tcagcccgga gcacgggccc 720 gttgtggtgc actgcagtgc aggcatcggc aggtctggaa ccttctgtct ggctgatacc 780 tgcctcctgc tgatggacaa gaggaaagac ccttcttccg ttgatatcaa gaaagtgctg 840 ttagaaatga ggaagtttcg gatggggttg atccagacag ccgaccagct gcgcttctcc 900 tacctggctg tgatcgaagg tgccaaattc atcatggggg actcttccgt gcaggatcag 960 tggaaggagc tttcccacga ggacctggag cccccacccg agcatatccc cccacctccc 1020 cggccaccca aacgaatcct ggagccacac aatgggaaat gcagggagtt cttcccaaat 1080 caccagtggg tgaaggaaga gacccaggag gataaagact gccccatcaa ggaagaaaaa 1140 ggaagcccct taaatgccgc accctacggc atcgaaagca tgagtcaaga cactgaagtt 1200 agaagtcggg tcgtgggggg aagtcttcga ggtgcccagg ctgcctcccc agccaaaggg 1260 gagccgtcac tgcccgagaa ggacgaggac catgcactga gttactggaa gcccttcctg 1320 gtcaacatgt gcgtggctac ggtcctcacg gccggcgctt acctctgcta caggttcctg 1380 ttcaacagca acacatagcc tgaccctcct ccactccacc tccacccact gtccgcctct 1440 gcccgcagag cccacgcccg actagcaggc atgccgcggt aggtaagggc cgccggaccg 1500 cgtagagagc cgggccccgg acggacgttg gttctgcact aaaacccatc ttccccggat 1560 gtgtgtctca cccctcatcc ttttactttt tgccccttcc actttgagta ccaaatccac 1620 aagccatttt ttgaggagag tgaaagagag taccatgctg gcggcgcaga gggaaggggc 1680 ctacacccgt cttggggctc gccccaccca gggctccctc ctggagcatc ccaggcggcg 1740 cacgccaaca gcccccccct tgaatctgca gggagcaact ctccactcca tatttattta 1800 aacaattttt tccccaaagg catccatagt gcactagcat tttcttgaac caataatgta 1860 ttaaaatttt ttgatgtcag ccttgcatca agggctttat caaaaagtac aataataaat 1920 cctcaggtag tactgggaat ggaaggcttt gccatgggcc tgctgcgtca gaccagtact 1980 gggaaggagg acggttgtaa gcagttgtta tttagtgata ttgtgggtaa cgtgagaaga 2040 tagaacaatg ctataatata taatgaacac gtgggtattt aataagaaac atgatgtgag 2100 attactttgt cccgcttatt ctcctccctg ttatctgcta gatctagttc tcaatcactg 2160 ctcccccgtg tgtattagaa tgcatgtaag gtcttcttgt gtcctgatga aaaatatgtg 2220 cttgaaatga gaaactttga tctctgctta ctaatgtgcc ccatgtccaa gtccaacctg 2280 cctgtgcatg acctgatcat tacatggctg tggttcctaa gcctgttgct gaagtcattg 2340 tcgctcagca atagggtgca gttttccagg aataggcatt tgctaattcc tggcatgaca 2400 ctctagtgac ttcctggtga ggcccagcct gtcctggtac agcagggtct tgctgtaact 2460 cagacattcc aagggtatgg gaagccatat tcacacctca cgctctggac atgatttagg 2520 gaagcaggga caccccccgc cccccacctt tgggatcagc ctccgccatt ccaagtcaac 2580 actcttcttg agcagaccgt gatttggaag agaggcacct gctggaaacc acacttcttg 2640 aaacagcctg ggtgacggtc ctttaggcag cctgccgccg tctctgtccc ggttcacctt 2700 gccgagagag gcgcgtctgc cccaccctca aaccctgtgg ggcctgatgg tgctcacgac 2760 tcttcctgca aagggaactg aagacctcca cattaagtgg ctttttaaca tgaaaaacac 2820 ggcagctgta gctcccgagc tactctcttg ccagcatttt cacattttgc ctttctcgtg 2880 gtagaagcca gtacagagaa attctgtggt gggaacattc gaggtgtcac cctgcagagc 2940 tatggtgagg tgtggataag gcttaggtgc caggctgtaa gcattctgag ctggcttgtt 3000 gtttttaagt cctgtatatg tatgtagtag tttgggtgtg tatatatagt agcatttcaa 3060 aatggacgta ctggtttaac ctcctatcct tggagagcag ctggctctcc accttgttac 3120 acattatgtt agagaggtag cgagctgctc tgctatatgc cttaagccaa tatttactca 3180 tcaggtcatt attttttaca atggccatgg aataaaccat ttttacaaaa ataaaaacaa 3240 aaaaagc 3247 <210> SEQ ID NO 8 <211> LENGTH: 435 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Glu Met Glu Lys Glu Phe Glu Gln Ile Asp Lys Ser Gly Ser Trp 1 5 10 15 Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe Pro Cys 20 25 30 Arg Val Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr Arg Asp 35 40 45 Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu Asp Asn 50 55 60 Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln Arg Ser 65 70 75 80 Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His Phe Trp 85 90 95 Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu Asn Arg 100 105 110 Val Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro Gln Lys 115 120 125 Glu Glu Lys Glu Met Ile Phe Glu Asp Thr Asn Leu Lys Leu Thr Leu 130 135 140 Ile Ser Glu Asp Ile Lys Ser Tyr Tyr Thr Val Arg Gln Leu Glu Leu 145 150 155 160 Glu Asn Leu Thr Thr Gln Glu Thr Arg Glu Ile Leu His Phe His Tyr 165 170 175 Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe Leu 180 185 190 Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Pro Glu His 195 200 205 Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 210 215 220 Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg Lys Asp 225 230 235 240 Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg Lys Phe 245 250 255 Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser Tyr Leu 260 265 270 Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser Val Gln 275 280 285 Asp Gln Trp Lys Glu Leu Ser His Glu Asp Leu Glu Pro Pro Pro Glu 290 295 300 His Ile Pro Pro Pro Pro Arg Pro Pro Lys Arg Ile Leu Glu Pro His 305 310 315 320 Asn Gly Lys Cys Arg Glu Phe Phe Pro Asn His Gln Trp Val Lys Glu 325 330 335 Glu Thr Gln Glu Asp Lys Asp Cys Pro Ile Lys Glu Glu Lys Gly Ser 340 345 350 Pro Leu Asn Ala Ala Pro Tyr Gly Ile Glu Ser Met Ser Gln Asp Thr 355 360 365 Glu Val Arg Ser Arg Val Val Gly Gly Ser Leu Arg Gly Ala Gln Ala 370 375 380 Ala Ser Pro Ala Lys Gly Glu Pro Ser Leu Pro Glu Lys Asp Glu Asp 385 390 395 400 His Ala Leu Ser Tyr Trp Lys Pro Phe Leu Val Asn Met Cys Val Ala 405 410 415 Thr Val Leu Thr Ala Gly Ala Tyr Leu Cys Tyr Arg Phe Leu Phe Asn 420 425 430 Ser Asn Thr 435 <210> SEQ ID NO 9 <211> LENGTH: 3215 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 gcgcgacgcg gcctagagcg gcagacggcg cagtgggccg agaaggaggc gcagcagccg 60 ccctggcccg tcatggagat ggaaaaggag ttcgagcaga tcgacaagtc cgggagctgg 120 gcggccattt accaggatat ccgacatgaa gccagtgact tcccatgtag agtggccaag 180 cttcctaaga acaaaaaccg aaataggtac agagacgtca gtccctttga ccatagtcgg 240 attaaactac atcaagaaga taatgactat atcaacgcta gtttgataaa aatggaagaa 300 gcccaaagga gttacattct tacccagggc cctttgccta acacatgcgg tcacttttgg 360 gagatggtgt gggagcagaa aagcaggggt gtcgtcatgc tcaacagagt gatggagaaa 420 ggttcgttaa aatgcgcaca atactggcca caaaaagaag aaaaagagat gatctttgaa 480 gacacaaatt tgaaattaac attgatctct gaagatatca agtcatatta tacagtgcga 540 cagctagaat tggaaaacct tacaacccaa gaaactcgag agatcttaca tttccactat 600 accacatggc ctgactttgg agtccctgaa tcaccagcct cattcttgaa ctttcttttc 660 aaagtccgag agtcagggtc actcagcccg gagcacgggc ccgttgtggt gcactgcagt 720 gcaggcatcg gcaggtctgg aaccttctgt ctggctgata cctgcctctt gctgatggac 780 aagaggaaag acccttcttc cgttgatatc aagaaagtgc tgttagaaat gaggaagttt 840 cggatggggc tgatccagac agccgaccag ctgcgcttct cctacctggc tgtgatcgaa 900 ggtgccaaat tcatcatggg ggactcttcc gtgcaggatc agtggaagga gctttcccac 960 gaggacctgg agcccccacc cgagcatatc cccccacctc cccggccacc caaacgaatc 1020 ctggagccac acaatgggaa atgcagggag ttcttcccaa atcaccagtg ggtgaaggaa 1080 gagacccagg aggataaaga ctgccccatc aaggaagaaa aaggaagccc cttaaatgcc 1140 gcaccctacg gcatcgaaag catgagtcaa gacactgaag ttagaagtcg ggtcgtgggg 1200 ggaagtcttc gaggtgccca ggctgcctcc ccagccaaag gggagccgtc actgcccgag 1260 aaggacgagg accatgcact gagttactgg aagcccttcc tggtcaacat gtgcgtggct 1320 acggtcctca cggccggcgc ttacctctgc tacaggttcc tgttcaacag caacacatag 1380 cctgaccctc ctccactcca cctccaccca ctgtccgcct ctgcccgcag agcccacgcc 1440 cgactagcag gcatgccgcg gtaggtaagg gccgccggac cgcgtagaga gccgggcccc 1500 ggacggacgt tggttctgca ctaaaaccca tcttccccgg atgtgtgtct cacccctcat 1560 ccttttactt tttgcccctt ccactttgag taccaaatcc acaagccatt ttttgaggag 1620 agtgaaagag agtaccatgc tggcggcgca gagggaaggg gcctacaccc gtcttggggc 1680 tcgccccacc cagggctccc tcctggagca tcccaggcgg gcggcacgcc agacagcccc 1740 ccccttgaat ctgcagggag caactctcca ctccatattt atttaaacaa ttttttcccc 1800 aaaggcatcc atagtgcact agcattttct tgaaccaata atgtattaaa attttttgat 1860 gtcagccttg catcaagggc tttatcaaaa agtacaataa taaatcctca ggtagtactg 1920 ggaatggaag gctttgccat gggcctgctg cgtcagacca gtactgggaa ggaggacggt 1980 tgtaagcagt tgttatttag tgatattgtg ggtaacgtga gaagatagaa caatgctata 2040 atatataatg aacacgtggg tatttaataa gaaacatgat gtgagattac tttgtcccgc 2100 ttattctgct ccctgttatc tgctagatct agttctcaat cactgctccc ccgtgtgtat 2160 tagaatgcat gtaaggtctt cttgtgtcct gatgaaaaat atgtgcttga aatgagaaac 2220 tttgatctct gcttactaat gtgccccatg tccaagtcca acctgcctgt gcatgacctg 2280 atcattacat ggctgtggtt cctaagcctg ttgctgaagt cattgtcgct cagcaatagg 2340 gtgcagtttt ccaggaatag gcatttgcct aattcctggc atgacactct agtgacttcc 2400 tggtgaggcc cagcctgtcc tggtacagca gggtcttgct gtaactcaga cattccaagg 2460 gtatgggaag ccatattcac acctcacgct ctggacatga tttagggaag cagggacacc 2520 ccccgccccc cacctttggg atcagcctcc gccattccaa gtcgacactc ttcttgagca 2580 gaccgtgatt tggaagagag gcacctgctg gaaaccacac ttcttgaaac agcctgggtg 2640 acggtccttt aggcagcctg ccgccgtctc tgtcccggtt caccttgccg agagaggcgc 2700 gtctgcccca ccctcaaacc ctgtggggcc tgatggtgct cacgactctt cctgcaaagg 2760 gaactgaaga cctccacatt aagtggcttt ttaacatgaa aaacacggca gctgtagctc 2820 ccgagctact ctcttgccag cattttcaca ttttgccttt ctcgtggtag aagccagtac 2880 agagaaattc tgtggtggga acattcgagg tgtcaccctg cagagctatg gtgaggtgtg 2940 gataaggctt aggtgccagg ctgtaagcat tctgagctgg cttgttgttt ttaagtcctg 3000 tatatgtatg tagtagtttg ggtgtgtata tatagtagca tttcaaaatg gacgtactgg 3060 tttaacctcc tatccttgga gagcagctgg ctctccacct tgttacacat tatgttagag 3120 aggtagcgag ctgctctgct atgtccttaa gccaatattt actcatcagg tcattatttt 3180 ttacaatggc catggaataa accattttta caaaa 3215 <210> SEQ ID NO 10 <211> LENGTH: 435 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Met Glu Met Glu Lys Glu Phe Glu Gln Ile Asp Lys Ser Gly Ser Trp 1 5 10 15 Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe Pro Cys 20 25 30 Arg Val Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr Arg Asp 35 40 45 Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu Asp Asn 50 55 60 Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln Arg Ser 65 70 75 80 Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His Phe Trp 85 90 95 Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu Asn Arg 100 105 110 Val Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro Gln Lys 115 120 125 Glu Glu Lys Glu Met Ile Phe Glu Asp Thr Asn Leu Lys Leu Thr Leu 130 135 140 Ile Ser Glu Asp Ile Lys Ser Tyr Tyr Thr Val Arg Gln Leu Glu Leu 145 150 155 160 Glu Asn Leu Thr Thr Gln Glu Thr Arg Glu Ile Leu His Phe His Tyr 165 170 175 Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe Leu 180 185 190 Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Pro Glu His 195 200 205 Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 210 215 220 Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg Lys Asp 225 230 235 240 Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg Lys Phe 245 250 255 Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser Tyr Leu 260 265 270 Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser Val Gln 275 280 285 Asp Gln Trp Lys Glu Leu Ser His Glu Asp Leu Glu Pro Pro Pro Glu 290 295 300 His Ile Pro Pro Pro Pro Arg Pro Pro Lys Arg Ile Leu Glu Pro His 305 310 315 320 Asn Gly Lys Cys Arg Glu Phe Phe Pro Asn His Gln Trp Val Lys Glu 325 330 335 Glu Thr Gln Glu Asp Lys Asp Cys Pro Ile Lys Glu Glu Lys Gly Ser 340 345 350 Pro Leu Asn Ala Ala Pro Tyr Gly Ile Glu Ser Met Ser Gln Asp Thr 355 360 365 Glu Val Arg Ser Arg Val Val Gly Gly Ser Leu Arg Gly Ala Gln Ala 370 375 380 Ala Ser Pro Ala Lys Gly Glu Pro Ser Leu Pro Glu Lys Asp Glu Asp 385 390 395 400 His Ala Leu Ser Tyr Trp Lys Pro Phe Leu Val Asn Met Cys Val Ala 405 410 415 Thr Val Leu Thr Ala Gly Ala Tyr Leu Cys Tyr Arg Phe Leu Phe Asn 420 425 430 Ser Asn Thr 435 <210> SEQ ID NO 11 <211> LENGTH: 4127 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 11 agccgctgct ggggaggttg gggctgaggt ggtggcgggc gacgggcctc gagacgcgga 60 gcgacgcggc ctagcgcggc ggacggccga gggaactcgg gcagtcgtcc cgtcccgcca 120 tggaaatgga gaaggaattc gagcagatcg ataaggctgg gaactgggcg gctatttacc 180 aggatattcg acatgaagcc agtgacttcc catgcagaat agcgaaactt cctaagaaca 240 aaaaccggaa caggtaccga gatgtcagcc cttttgacca cagtcggatt aaattgcatc 300 aggaagataa tgactatatc aatgccagct tgataaaaat ggaggaagcc cagaggagct 360 atatcctcac ccagggccct ttaccaaaca cgtgcgggca cttctgggag atggtgtggg 420 agcagaagag caggggcgtg gtcatgctca accgcatcat ggagaaaggc tcgttaaaat 480 gtgcccagta ttggccacag aaagaagaaa aagagatggt cttcgatgac accaatttga 540 agctgacact gatctctgaa gatgtcaagt catattacac agtacggcag ttggagttgg 600 agaacctggc tacccaggag gctcgagaga tcctgcattt ccactacacc acctggcctg 660 actttggagt ccctgagtca cctgcctctt tcctcaattt cctattcaaa gtccgagagt 720 caggctcact cagcccagag cacggcccca ttgtggtcca ctgcagtgct ggcattggca 780 ggtcagggac cttctgcctg gctgacacct gcctcttact gatggacaag aggaaagacc 840 cgtcctctgt ggacatcaag aaagtgctgt tggagatgcg caggttccgc atggggctca 900 tccagacggc cgaccaactg cgcttctcct acctggctgt gatcgagggt gcaaagttca 960 tcatgggcga ctcgtcagtg caggatcagt ggaaggagct ttcccatgaa gacctggagc 1020 ctccccctga gcacgtgccc ccacctcccc ggccacccaa acgcacattg gagcctcaca 1080 atggcaagtg caaggagctc ttctccaacc accagtgggt gagcgaggag agctgtgagg 1140 atgaggacat cctggccaga gaggaaagca gagccccctc aattgctgtg cacagcatga 1200 gcagtatgag tcaagacact gaagttagga aacggatggt gggtggaggt cttcaaagtg 1260 ctcaggcatc tgtccccact gaggaagagc tgtccccaac cgaggaggaa caaaaggcac 1320 acaggccagt tcactggaag cccttcctgg tcaacgtgtg catggccacg gccctggcga 1380 ctggcgcgta cctctgttac cgggtatgtt ttcactgaca gactgctgtg aggcatgagc 1440 gtggtgggcg ctgccactgc ccaggttagg atttggtctg cggcgtctaa cctggtgtag 1500 aagaaacaac agcttacaag cctgtggtgg aactggaagg gccagcccca ggaggggcat 1560 ctgtgcactg ggctttgaag gagcccctgg tcccaagaac agagtctaat ctcagggcct 1620 taacctgttc aggagaagta gaggaaatgc caaatactct tcttgctctc acctcactcc 1680 tcccctttct ctggttcgtt tgtttttgga aaaaaaaaaa aaagaattac aacacattgt 1740 tgtttttaac atttataaag gcaggttttt gttattttta gagaaaacaa aagatgctag 1800 gcactggtga gattctcttg tgccctttgg catgtgatca gattcacgat ttacgtttat 1860 ttccggggga gggtcccacc tgtcaggact gtaaagttcc tgctggcttg gtcagccccc 1920 ccaccccccc accccgagct tgcaggtgcc ctgctgtgag gagagcagca gcagaggctg 1980 cccctggaca gaagcccagc tctgcttccc tcaggtgtcc ctgcgtttcc atcctccttc 2040 tttgtgaccg ccatcttgca gatgacccag tcctcagcac cccacccctg cagatgggtt 2100 tctccgaggg cctgcctcag ggtcatcaga ggttggctgc cagcttagag ctggggcttc 2160 catttgattg gaaagtcatt actattctat gtagaagcca ctccactgag gtgtaaagca 2220 agactcataa aggaggagcc ttggtgtcat ggaagtcact ccgcgcgcag gacctgtaac 2280 aacctctgaa acactcagtc ctgctgcagt gacgtccttg aaggcatcag acagatgatt 2340 tgcagactgc caagacttgt cctgagccgt gatttttaga gtctggactc atgaaacacc 2400 gccgagcgct tactgtgcag cctctgatgc tggttggctg aggctgcggg gaggtggaca 2460 ctgtgggtgc atccagtgca gttgcttttg tgcagttggg tccagcagca cagcccgcac 2520 tccagcctca gctgcaggcc acagtggcca tggaggccgc cagagcgagc tggggtggat 2580 gcttgttcac ttggagcagc cttcccagga cgtgcagctc ccttcctgct ttgtccttct 2640 gcttccttcc ctggagtagc aagcccacga gcaatcgtga ggggtgtgag ggagctgcag 2700 aggcatcaga gtggcctgca gcggcgtgag gccccttccc ctccgacacc cccctccaga 2760 ggagccgctc cactgttatt tattcacttt gcccacagac acccctgagt gagcacaccc 2820 tgaaactgac cgtgtaaggt gtcagcctgc acccaggacc gtcaggtgca gcaccgggtc 2880 agtcctaggg ttgaggtagg actgacacag ccactgtgtg gctggtgctg gggcaggggc 2940 aggagctgag ggtcttagaa gcaatcttca ggaacagaca acagtggtga catgtaaagt 3000 ccctgtggct actgatgaca tgtgtaggat gaaggctggc ctttctccca tgactttcta 3060 gatcccgttc cccgtctgct ttccctgtga gttagaaaac acacaggctc ctgtcctggt 3120 ggtgccgtgt gcttgacatg ggaaacttag atgcctgctc actggcgggc acctcggcat 3180 cgccaccact cagagtgaga gcagtgctgt ccagtgccga ggccgcctga ctcccggcag 3240 gactcttcag gctctggcct gccccagcac accccgctgg atctcagaca ttccacaccc 3300 acacctcatt ccctggacac ttgggcaagc aggcccgccc ttccacctct ggggtcagcc 3360 cctccattcc gagttcacac tgctctggag caggccagga ccggaagcaa ggcagctggt 3420 gaggagcacc ctcctgggaa cagtgtaggt gacagtcctg agagtcagct tgctagcgct 3480 gctggcacca gtcaccttgc tcagaagtgt gtggctcttg aggctgaaga gactgatgat 3540 ggtgctcatg actcttctgt gaggggaact tgaccttcac attgggtggc tttttttaaa 3600 ataagcgaag gcagctggaa ctccagtctg cctcttgcca gcacttcaca ttttgccttt 3660 cacccagaga agccagcaca gagccactgg ggaaggcgat ggccttgcct gcacaggctg 3720 aggagatggc tcagccggcg tccaggctgt gtctggagca gggggtgcac agcagcctca 3780 caggtggggg cctcagagca ggcgctgccc tgtcccctgc cccgctggag gcagcaaagc 3840 tgctgcatgc cttaagtcaa tacttactca gcagggcgct ctcgttctct ctctctctct 3900 ctctctctct ctctctctct ctctctctct ctctaaatgg ccatagaata aaccatttta 3960 caaaaataaa agccaacaac aaagtgctct ggaatagcac ctttgcagga gcggggggtg 4020 tctcagggtc ttctgtgacc tcaccgaact gtccgactgc accgtttcca acttgtgtct 4080 cactaatggg tctgcattag ttgcaacaat aaatgttttt aaagaac 4127 <210> SEQ ID NO 12 <211> LENGTH: 432 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 12 Met Glu Met Glu Lys Glu Phe Glu Gln Ile Asp Lys Ala Gly Asn Trp 1 5 10 15 Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe Pro Cys 20 25 30 Arg Ile Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr Arg Asp 35 40 45 Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu Asp Asn 50 55 60 Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln Arg Ser 65 70 75 80 Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His Phe Trp 85 90 95 Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu Asn Arg 100 105 110 Ile Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro Gln Lys 115 120 125 Glu Glu Lys Glu Met Val Phe Asp Asp Thr Asn Leu Lys Leu Thr Leu 130 135 140 Ile Ser Glu Asp Val Lys Ser Tyr Tyr Thr Val Arg Gln Leu Glu Leu 145 150 155 160 Glu Asn Leu Ala Thr Gln Glu Ala Arg Glu Ile Leu His Phe His Tyr 165 170 175 Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe Leu 180 185 190 Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Pro Glu His 195 200 205 Gly Pro Ile Val Val His Cys Ser Ala Gly Ile Gly Arg Ser Gly Thr 210 215 220 Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg Lys Asp 225 230 235 240 Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg Arg Phe 245 250 255 Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser Tyr Leu 260 265 270 Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser Val Gln 275 280 285 Asp Gln Trp Lys Glu Leu Ser His Glu Asp Leu Glu Pro Pro Pro Glu 290 295 300 His Val Pro Pro Pro Pro Arg Pro Pro Lys Arg Thr Leu Glu Pro His 305 310 315 320 Asn Gly Lys Cys Lys Glu Leu Phe Ser Asn His Gln Trp Val Ser Glu 325 330 335 Glu Ser Cys Glu Asp Glu Asp Ile Leu Ala Arg Glu Glu Ser Arg Ala 340 345 350 Pro Ser Ile Ala Val His Ser Met Ser Ser Met Ser Gln Asp Thr Glu 355 360 365 Val Arg Lys Arg Met Val Gly Gly Gly Leu Gln Ser Ala Gln Ala Ser 370 375 380 Val Pro Thr Glu Glu Glu Leu Ser Pro Thr Glu Glu Glu Gln Lys Ala 385 390 395 400 His Arg Pro Val His Trp Lys Pro Phe Leu Val Asn Val Cys Met Ala 405 410 415 Thr Ala Leu Ala Thr Gly Ala Tyr Leu Cys Tyr Arg Val Cys Phe His 420 425 430 <210> SEQ ID NO 13 <211> LENGTH: 2229 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 13 ggtaccccgc ggagcctgag cgagcaggcg tccgtgcgga gccgaagacg ggaggaacat 60 gacatcgcgg agatggtttc accccaacat cactggtgtg gaggcagaga atctcctgct 120 gaccagagga gtcgatggca gttttttagc aaggcccagt aagagtaacc ctggagactt 180 cactctgtct gttagaagaa atggagctgt tacccacatc aagattcaga acactgggga 240 ctactatgac ctctatggtg gggagaagtt tgccactttg gctgaactgg ttcagtatta 300 catggaacac catgggcagc tgaaagagaa gaatggagat gttatcgagc tcaagtaccc 360 gctgaactgt gcagacccta cctctgaaag gtggttccat ggtcacttgt ctggaaaaga 420 agcagagaag ctgctgacgg agaagggcaa gcatggcagc ttcctcgttc gagagagcca 480 gagccacccc ggagacttcg ttctctccgt gcgcactggt gacgacaaag gggagagcaa 540 cgacggcaag tccaaagtga cccacgtcat gatccgctgt caggagctga aatacgacgt 600 tggtggggga gagcgctttg actctctgac agacctggtg gagcattaca agaagaaccc 660 catggtggag acgctgggca cagtcctgca gctcaagcag cccctcaaca caactcgtat 720 caatgctgct gaaattgaaa gccgggttcg agagttaagc aagctggctg agaccacaga 780 taaagtcaag cagggctttt gggaagagtt tgagacgctc cagcaacagg aatgcaaact 840 tctctatagc cgaaaagaag gacagagaca agaaaataaa aacaaaaaca gatacaaaaa 900 catcctgccc tttgatcata ccagggtcgt tctgcatgat ggggatccca atgagcctgt 960 ttctgattac attaatgcaa acatcatcat gcctgagttt gagaccaagt gcaacaattc 1020 caaacccaaa aagagttaca ttgccactca aggctgcctg cagaacacgg tgaatgactt 1080 ctggcggatg gtgttccagg agaactctcg agtcattgtc atgaccacaa aggaagtgga 1140 gagagggaag agcaaatgtg tcaagtactg gcctgatgag tatgcgctca aagaatacgg 1200 ggtcatgcgt gttaggaacg tcaaagaaag tgccgcccat gactacactt tacgagagct 1260 caaactctct aaggtcggac aagctctact ccagggaaac acagagagaa ccgtctggca 1320 gtaccacttt cggacctggc cagaccatgg cgtgcctagt gaccctggag gtgtgctgga 1380 cttcctggag gaggtccacc acaagcagga gagcatcgtg gatgcaggcc ctgtcgtggt 1440 tcactgcagc gctgggattg gccggacagg aaccttcatt gtgattgaca tccttattga 1500 catcattcga gagaaaggtg tggactgtga catcgacgtt cctaaaacca ttcagatggt 1560 gcggtcccag aggtcgggga tggtccagac agaagcacag taccggttta tctacatggc 1620 tgtccagcac tacatagaga cgctgcagcg ccggatcgag gaggagcaga aaagcaaaag 1680 aaaaggacat gaatatacca atattaagta ttccttggtg gaccagacaa gtggtgatca 1740 gagtcccctg ccaccctgca ccccaacgcc accctgtgca gaaatgaggg aggacagcgc 1800 ccgagtctat gagaacgtgg gcctcatgca gcagcagagg agtttcagat gagcccacgg 1860 cgacagaacg cagatgtgaa ctttcacccc tttcctaaaa tgtcaagact agacgagcgt 1920 tcccaggacc cgtgcgtgcg ttcagaagcc ggcactggct ggactgcctc ttgagaagcg 1980 aagtttggaa ccatttgaac agcacgtgcc taattggcac ctcctttcct cagctaagga 2040 gagactgctc tgcgttcttg acaatgctat tttcatagaa ttggttttga attgtggaag 2100 cagctaaatt gtgctctgta ttttctacat tatgggactc aaattctagt tatgggcagg 2160 attttgtttc tttttatgac cttaacagat ctgatttttt ttttctttct ctctctttgg 2220 ggaatcatg 2229 <210> SEQ ID NO 14 <211> LENGTH: 597 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 14 Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala 1 5 10 15 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn 35 40 45 Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr 65 70 75 80 Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile 85 90 95 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp 100 105 110 Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu 115 120 125 Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser 145 150 155 160 Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu 165 170 175 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp 180 185 190 Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr 195 200 205 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Ala 210 215 220 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Lys Leu Ala Glu Thr Thr 225 230 235 240 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Phe Glu Thr Leu Gln Gln 245 250 255 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Glu Gly Gln Arg Gln Glu 260 265 270 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Thr 275 280 285 Arg Val Val Leu His Asp Gly Asp Pro Asn Glu Pro Val Ser Asp Tyr 290 295 300 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Glu Thr Lys Cys Asn Asn 305 310 315 320 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gln Gly Cys Leu Gln Asn 325 330 335 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gln Glu Asn Ser Arg Val 340 345 350 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gly Lys Ser Lys Cys Val 355 360 365 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Glu Tyr Gly Val Met Arg 370 375 380 Val Arg Asn Val Lys Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 385 390 395 400 Leu Lys Leu Ser Lys Val Gly Gln Ala Leu Leu Gln Gly Asn Thr Glu 405 410 415 Arg Thr Val Trp Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val 420 425 430 Pro Ser Asp Pro Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His 435 440 445 Lys Gln Glu Ser Ile Val Asp Ala Gly Pro Val Val Val His Cys Ser 450 455 460 Ala Gly Ile Gly Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Leu Ile 465 470 475 480 Asp Ile Ile Arg Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pro Lys 485 490 495 Thr Ile Gln Met Val Arg Ser Gln Arg Ser Gly Met Val Gln Thr Glu 500 505 510 Ala Gln Tyr Arg Phe Ile Tyr Met Ala Val Gln His Tyr Ile Glu Thr 515 520 525 Leu Gln Arg Arg Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gly His 530 535 540 Glu Tyr Thr Asn Ile Lys Tyr Ser Leu Val Asp Gln Thr Ser Gly Asp 545 550 555 560 Gln Ser Pro Leu Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Glu Met 565 570 575 Arg Glu Asp Ser Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gln Gln 580 585 590 Gln Arg Ser Phe Arg 595 <210> SEQ ID NO 15 <211> LENGTH: 2236 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 15 cgggctcccg agcggggcct cactcggccc cctccatgtg acggcgcctc gtggagcctg 60 agtgagcagc gggtccgtgc ggagccggag gcgggaggaa catgacatcc cggagatggt 120 ttcaccccaa tatcactggt gtggaggcag agaatctcct gctgacccga ggagtcgatg 180 gcagtttctt agcgaggccc agcaagagta accctggaga cttcactctg tctgttagaa 240 gaaatggagc cgttacccac atcaagattc agaacactgg ggactactat gacctctatg 300 gcggggaaaa gtttgccacc ttgcctgaac tggtccagta ttacatggag catcacgggc 360 agctgaaaga gaagaatgga gatgttattg agctcaagta cccactgaac tgtgcagacc 420 ctacctctga aaggtggttc cacggtcact tgtctggaaa agaagcagag aagctgctga 480 cagagaaggg gaagcatggc agtttcctcg tccgggagag ccagagccac cctggggact 540 tcgtcctctc cgtccgcact ggtgatgaca aaggggagag caatgacagc aagtccaaag 600 tgacccatgt catgatccgc tgtcaggagc tgaaatatga tgttggtgga ggagagcgct 660 ttgactcttt gacagacctg gtggagcatt acaagaagaa ccccatggtg gagacactgg 720 gcacagtcct gcagctcaaa cagcccctca acacaactcg tattaatgcc gctgaaatcg 780 aaagccgggt tcgggagtta agcaagctag ccgagaccac agataaagtc aaacagggct 840 tttgggaaga atttgagact ctacagcaac aggaatgcaa acttctctac agccgaaaag 900 aaggacagag acaagaaaat aaaaacaaaa atagatacaa aaacatcctg ccctttgatc 960 ataccagggt tgtcctgcac gatggggatc ccaacgagcc agtttctgat tacatcaatg 1020 ccaacatcat catgcctgaa tttgaaacca agtgcaacaa ttcaaaaccc aaaaagagtt 1080 acattgccac tcaaggctgc ctgcagaaca cggtgaatga cttctggcgg atggtgttcc 1140 aggagaactc tcgagtcatt gtcatgacca caaaggaagt ggagagaggg aagagcaagt 1200 gtgtcaagta ctggcctgat gagtgtgcac tcaaagagta tggcgtcatg cgtgtgagga 1260 acgtcagaga aagtgctgcg catgactaca ccttacgaga actcaaactc tctaaggtcg 1320 gacaaggaaa cacagagaga accgtctggc agtaccactt tcggacctgg ccagaccacg 1380 gtgtgcctag tgaccctgga ggtgtgctgg acttcctgga ggaggtccac cacaagcagg 1440 agagcatcgt ggatgcaggc cctgtcgtgg ttcactgcag tgctgggatt ggccggacag 1500 gaacgttcat tgtgattgat atccttattg acatcatccg agagaaaggt gtggactgtg 1560 acatcgacgt tcctaaaacc attcagatgg tacggtccca gaggtcaggg atggtccaga 1620 cagaagcaca gtaccggttc atctacatgg ccgtccagca ctacatagag acgctgcaac 1680 gcaggatcga ggaggagcag aaaagcaaaa ggaaaggaca tgaatatacc aatattaagt 1740 attccctggt ggaccagaca agtggcgatc agagtcccct gccaccttgc accccaacgc 1800 caccctgtgc ggaaatgcgg gaggacagcg ctcgagtcta tgagaacgtg ggcctcatgc 1860 agcagcagag gagtttcaga tgagcttcgg gtggcagcgc gcagatgtga actttcaccc 1920 cttccctaaa atgtcaagaa tagacgagaa agtttccagg acccgtgttc agaagctcgc 1980 cggggttgac tgactgcctt ttgagaagcg aagtttggaa ccatttgaaa gagcacgtgc 2040 ctaattggca cctcctttcc tcagctaagg agaaactgct ctgcgttgtc gacagtgcta 2100 ttgtcatgga attggttttg aattgtgaag cagctaaatt gtgctctgta ttttctacat 2160 tgtgggactc aaattctagt cacgggcagg attttgtttg tttcttttta tgaccttaac 2220 agacctgtta agaccg 2236 <210> SEQ ID NO 16 <211> LENGTH: 593 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 16 Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala 1 5 10 15 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn 35 40 45 Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Pro Glu Leu Val Gln Tyr 65 70 75 80 Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile 85 90 95 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp 100 105 110 Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu 115 120 125 Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser 145 150 155 160 Asn Asp Ser Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu 165 170 175 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp 180 185 190 Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr 195 200 205 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Ala 210 215 220 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Lys Leu Ala Glu Thr Thr 225 230 235 240 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Phe Glu Thr Leu Gln Gln 245 250 255 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Glu Gly Gln Arg Gln Glu 260 265 270 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Thr 275 280 285 Arg Val Val Leu His Asp Gly Asp Pro Asn Glu Pro Val Ser Asp Tyr 290 295 300 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Glu Thr Lys Cys Asn Asn 305 310 315 320 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gln Gly Cys Leu Gln Asn 325 330 335 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gln Glu Asn Ser Arg Val 340 345 350 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gly Lys Ser Lys Cys Val 355 360 365 Lys Tyr Trp Pro Asp Glu Cys Ala Leu Lys Glu Tyr Gly Val Met Arg 370 375 380 Val Arg Asn Val Arg Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 385 390 395 400 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Thr Glu Arg Thr Val Trp 405 410 415 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro 420 425 430 Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser 435 440 445 Ile Val Asp Ala Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly 450 455 460 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Leu Ile Asp Ile Ile Arg 465 470 475 480 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pro Lys Thr Ile Gln Met 485 490 495 Val Arg Ser Gln Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Arg 500 505 510 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Glu Thr Leu Gln Arg Arg 515 520 525 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gly His Glu Tyr Thr Asn 530 535 540 Ile Lys Tyr Ser Leu Val Asp Gln Thr Ser Gly Asp Gln Ser Pro Leu 545 550 555 560 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Glu Met Arg Glu Asp Ser 565 570 575 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gln Gln Gln Arg Ser Phe 580 585 590 Arg <210> SEQ ID NO 17 <211> LENGTH: 2287 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 ggggggcctg agcctctccg ccggcgcagg ctctgctcgc gccagctcgc tcccgcagcc 60 atgcccacca ccatcgagcg ggagttcgaa gagttggata ctcagcgtcg ctggcagccg 120 ctgtacttgg aaattcgaaa tgagtcccat gactatcctc atagagtggc caagtttcca 180 gaaaacagaa atcgaaacag atacagagat gtaagcccat atgatcacag tcgtgttaaa 240 ctgcaaaatg ctgagaatga ttatattaat gccagtttag ttgacataga agaggcacaa 300 aggagttaca tcttaacaca gggtccactt cctaacacat gctgccattt ctggcttatg 360 gtttggcagc agaagaccaa agcagttgtc atgctgaacc gcattgtgga gaaagaatcg 420 gttaaatgtg cacagtactg gccaacagat gaccaagaga tgctgtttaa agaaacagga 480 ttcagtgtga agctcttgtc agaagatgtg aagtcgtatt atacagtaca tctactacaa 540 ttagaaaata tcaatagtgg tgaaaccaga acaatatctc actttcatta tactacctgg 600 ccagattttg gagtccctga atcaccagct tcatttctca atttcttgtt taaagtgaga 660 gaatctggct ccttgaaccc tgaccatggg cctgcggtga tccactgtag tgcaggcatt 720 gggcgctctg gcaccttctc tctggtagac acttgtcttg ttttgatgga aaaaggagat 780 gatattaaca taaaacaagt gttactgaac atgagaaaat accgaatggg tcttattcag 840 accccagatc aactgagatt ctcatacatg gctataatag aaggagcaaa atgtataaag 900 ggagattcta gtatacagaa acgatggaaa gaactttcta aggaagactt atctcctgcc 960 tttgatcatt caccaaacaa aataatgact gaaaaataca atgggaacag aataggtcta 1020 gaagaagaaa aactgacagg tgaccgatgt acaggacttt cctctaaaat gcaagataca 1080 atggaggaga acagtgagag tgctctacgg aaacgtattc gagaggacag aaaggccacc 1140 acagctcaga aggtgcagca gatgaaacag aggctaaatg agaatgaacg aaaaagaaaa 1200 aggtggttat attggcaacc tattctcact aagatggggt ttatgtcagt cattttggtt 1260 ggcgcttttg ttggctggag actgtttttt cagcaaaatg ccctataaac aattaatttt 1320 gcccagcaag cttctgcact agtaactgac agtgctacat taatcatagg ggtttgtctg 1380 cagcaaacgc ctcatatccc aaaaacggtg cagtagaata gacatcaacc agataagtga 1440 tatttacagt cacaagccca acatctcagg actcttgact gcaggttcct ctgaacccca 1500 aactgtaaat ggctgtctaa aataaagaca ttcatgtttg ttaaaaactg gtaaattttg 1560 caactgtatt catacatgtc aaacacagta tttcacctga ccaacattga gatatccttt 1620 atcacaggat ttgtttttgg aggctatctg gattttaacc tgcacttgat ataagcaata 1680 aatattgtgg ttttatctac gttattggaa agaaaatgac atttaaataa tgtgtgtaat 1740 gtataatgta ctattgacat gggcatcaac acttttattc ttaagcattt cagggtaaat 1800 atattttata agtatctatt taatcttttg tagttaactg tactttttaa gagctcaatt 1860 tgaaaaatct gttactaaaa aaaaaaattg tatgtcgatt gaattgtact ggatacattt 1920 tccatttttc taaaaagaag tttgatatga gcagttagaa gttggaataa gcaatttcta 1980 ctatatattg catttctttt atgttttaca gttttcccca ttttaaaaag aaaagcaaac 2040 aaagaaacaa aagtttttcc taaaaatatc tttgaaggaa aattctcctt actgggatag 2100 tcaggtaaac agttggtcaa gactttgtaa agaaattggt ttctgtaaat cccattattg 2160 atatgtttat ttttcatgaa aatttcaatg tagttggggt agattatgat ttaggaagca 2220 aaagtaagaa gcagcatttt atgattcata atttcagttt actagactga agttttgaag 2280 taaaccc 2287 <210> SEQ ID NO 18 <211> LENGTH: 415 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Pro Thr Thr Ile Glu Arg Glu Phe Glu Glu Leu Asp Thr Gln Arg 1 5 10 15 Arg Trp Gln Pro Leu Tyr Leu Glu Ile Arg Asn Glu Ser His Asp Tyr 20 25 30 Pro His Arg Val Ala Lys Phe Pro Glu Asn Arg Asn Arg Asn Arg Tyr 35 40 45 Arg Asp Val Ser Pro Tyr Asp His Ser Arg Val Lys Leu Gln Asn Ala 50 55 60 Glu Asn Asp Tyr Ile Asn Ala Ser Leu Val Asp Ile Glu Glu Ala Gln 65 70 75 80 Arg Ser Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Cys His 85 90 95 Phe Trp Leu Met Val Trp Gln Gln Lys Thr Lys Ala Val Val Met Leu 100 105 110 Asn Arg Ile Val Glu Lys Glu Ser Val Lys Cys Ala Gln Tyr Trp Pro 115 120 125 Thr Asp Asp Gln Glu Met Leu Phe Lys Glu Thr Gly Phe Ser Val Lys 130 135 140 Leu Leu Ser Glu Asp Val Lys Ser Tyr Tyr Thr Val His Leu Leu Gln 145 150 155 160 Leu Glu Asn Ile Asn Ser Gly Glu Thr Arg Thr Ile Ser His Phe His 165 170 175 Tyr Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe 180 185 190 Leu Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Asn Pro Asp 195 200 205 His Gly Pro Ala Val Ile His Cys Ser Ala Gly Ile Gly Arg Ser Gly 210 215 220 Thr Phe Ser Leu Val Asp Thr Cys Leu Val Leu Met Glu Lys Gly Asp 225 230 235 240 Asp Ile Asn Ile Lys Gln Val Leu Leu Asn Met Arg Lys Tyr Arg Met 245 250 255 Gly Leu Ile Gln Thr Pro Asp Gln Leu Arg Phe Ser Tyr Met Ala Ile 260 265 270 Ile Glu Gly Ala Lys Cys Ile Lys Gly Asp Ser Ser Ile Gln Lys Arg 275 280 285 Trp Lys Glu Leu Ser Lys Glu Asp Leu Ser Pro Ala Phe Asp His Ser 290 295 300 Pro Asn Lys Ile Met Thr Glu Lys Tyr Asn Gly Asn Arg Ile Gly Leu 305 310 315 320 Glu Glu Glu Lys Leu Thr Gly Asp Arg Cys Thr Gly Leu Ser Ser Lys 325 330 335 Met Gln Asp Thr Met Glu Glu Asn Ser Glu Ser Ala Leu Arg Lys Arg 340 345 350 Ile Arg Glu Asp Arg Lys Ala Thr Thr Ala Gln Lys Val Gln Gln Met 355 360 365 Lys Gln Arg Leu Asn Glu Asn Glu Arg Lys Arg Lys Arg Trp Leu Tyr 370 375 380 Trp Gln Pro Ile Leu Thr Lys Met Gly Phe Met Ser Val Ile Leu Val 385 390 395 400 Gly Ala Phe Val Gly Trp Arg Leu Phe Phe Gln Gln Asn Ala Leu 405 410 415 <210> SEQ ID NO 19 <211> LENGTH: 462 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 cggaaacgta ttcgagagga cagaaaggcc accacagctc agaaggtgca gcagatgaaa 60 cagaggctaa atgagaatga acgaaaaaga aaaaggccaa gattgacaga cacctaatat 120 tcatgactta agaatattct gcagctataa attttgaacc attgatgtgc aaagcaagac 180 ctgaagccca ctccggaaac taaagtgagg ctcgctaacc ctctagattg cctcacagtt 240 gtttgtttac aaagtaaact ttacatccag gggatgaaga gcacccacca gcagaagact 300 ttgcagaacc tttaattgga tgtgttaagt gtttttaatg agtgtatgaa atgtagaaag 360 atgtacaaga aataaattag gagagattac tttgtattgt actgccattc ctactgtatt 420 tttatacttt ttggcagcat taaatatttt tgttaaatag tc 462 <210> SEQ ID NO 20 <211> LENGTH: 462 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 cggaaacgta ttcgagagga cagaaaggcc accacagctc agaaggtgca gcagatgaaa 60 cagaggctaa atgagaatga acgaaaaaga aaaaggccaa gattgacaga cacctaatat 120 tcatgactta agaatattct gcagctataa attttgaacc attgatgtgc aaagcaagac 180 ctgaagccca ctccggaaac taaagtgagg ctcgctaacc ctctagattg cctcacagtt 240 gtttgtttac aaagtaaact ttacatccag gggatgaaga gcacccacca gcagaagact 300 ttgcagaacc tttaattgga tgtgttaagt gtttttaatg agtgtatgaa atgtagaaag 360 atgtacaaga aataaattag gagagattac tttgtattgt actgccattc ctactgtatt 420 tttatacttt ttggcagcat taaatatttt tgttaaatag tc 462 <210> SEQ ID NO 21 <211> LENGTH: 1555 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 21 tctccccgga tagagcgggg cccgagcctg tccgctgtgg tagttccgct cggctgcccc 60 gccgccatgt cggcaaccat cgagcgggag ttcgaggaac tggatgctca gtgtcgctgg 120 cagccgttat acttggaaat tcgaaatgaa tcccatgact atcctcatag agtggccaag 180 tttccagaaa acagaaaccg aaacagatac agagatgtaa gcccatatga tcacagtcgt 240 gttaaactgc aaagtactga aaatgattat attaatgcca gcttagttga catagaagag 300 gcacaaagaa gttacatctt aacacagggc ccacttccga acacatgctg ccatttctgg 360 ctcatggtgt ggcagcaaaa gaccaaagca gttgtcatgc taaaccgaac tgtagaaaaa 420 gaatcggtta aatgtgcaca gtactggcca acggatgaca gagaaatggt gtttaaggaa 480 acgggattca gtgtgaagct cttatctgaa gatgtaaaat catattatac agtacatcta 540 ctacagttag aaaatatcaa tactggtgaa acgagaacca tatctcactt ccattatacc 600 acctggccag attttggggt tccagagtca ccagcttcat ttctaaactt cttgtttaaa 660 gttagagaat ctggttgttt gacccctgac catggacctg cagtgatcca ttgcagtgcg 720 ggcatcgggc gctctggcac cttctctctt gtagatacct gtcttgttct gatggaaaaa 780 ggagaggatg ttaatgtgaa acaattatta ctgaatatga gaaagtatcg aatgggactt 840 attcagacac cggaccaact cagattctcc tacatggcca taatagaagg agcaaagtac 900 acaaaaggag attcaaatat acagaaacgg tggaaagaac tttctaaaga agatttatct 960 cctatttgtg atcattcaca gaacagagtg atggttgaga agtacaatgg gaagagaata 1020 ggttcagaag atgaaaagtt aacagggctt ccttctaagg tgcaggatac tgtggaggag 1080 agcagtgaga gcattctacg gaaacgtatt cgagaggata gaaaggctac gacggctcag 1140 aaggtgcagc agatgaaaca gaggctaaat gaaactgaac gaaaaagaaa aaggccaaga 1200 ttgacagaca cctaaatgtt catgacttga gactattctg cagctataaa atttgaacct 1260 ttgatgtgca aagcaagacc tgaagcccac tccggaaact aaagtgaggc ttgctaaccc 1320 tgtagattgc ctcacaagtt gtctgtttac aaagtaagct ttccatccag gggatgaaga 1380 acgccaccag cagaagactt gcaaaccctt taatttgatg tattgttttt taacatgtgt 1440 atgaaatgta gaaagatgta aaggaaataa attaggagcg actactttgt attgtactgc 1500 cattcctaat gtatttttat actttttggc agcattaaat atttttatta aatag 1555 <210> SEQ ID NO 22 <211> LENGTH: 382 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 22 Met Ser Ala Thr Ile Glu Arg Glu Phe Glu Glu Leu Asp Ala Gln Cys 1 5 10 15 Arg Trp Gln Pro Leu Tyr Leu Glu Ile Arg Asn Glu Ser His Asp Tyr 20 25 30 Pro His Arg Val Ala Lys Phe Pro Glu Asn Arg Asn Arg Asn Arg Tyr 35 40 45 Arg Asp Val Ser Pro Tyr Asp His Ser Arg Val Lys Leu Gln Ser Thr 50 55 60 Glu Asn Asp Tyr Ile Asn Ala Ser Leu Val Asp Ile Glu Glu Ala Gln 65 70 75 80 Arg Ser Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Cys His 85 90 95 Phe Trp Leu Met Val Trp Gln Gln Lys Thr Lys Ala Val Val Met Leu 100 105 110 Asn Arg Thr Val Glu Lys Glu Ser Val Lys Cys Ala Gln Tyr Trp Pro 115 120 125 Thr Asp Asp Arg Glu Met Val Phe Lys Glu Thr Gly Phe Ser Val Lys 130 135 140 Leu Leu Ser Glu Asp Val Lys Ser Tyr Tyr Thr Val His Leu Leu Gln 145 150 155 160 Leu Glu Asn Ile Asn Thr Gly Glu Thr Arg Thr Ile Ser His Phe His 165 170 175 Tyr Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe 180 185 190 Leu Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Cys Leu Thr Pro Asp 195 200 205 His Gly Pro Ala Val Ile His Cys Ser Ala Gly Ile Gly Arg Ser Gly 210 215 220 Thr Phe Ser Leu Val Asp Thr Cys Leu Val Leu Met Glu Lys Gly Glu 225 230 235 240 Asp Val Asn Val Lys Gln Leu Leu Leu Asn Met Arg Lys Tyr Arg Met 245 250 255 Gly Leu Ile Gln Thr Pro Asp Gln Leu Arg Phe Ser Tyr Met Ala Ile 260 265 270 Ile Glu Gly Ala Lys Tyr Thr Lys Gly Asp Ser Asn Ile Gln Lys Arg 275 280 285 Trp Lys Glu Leu Ser Lys Glu Asp Leu Ser Pro Ile Cys Asp His Ser 290 295 300 Gln Asn Arg Val Met Val Glu Lys Tyr Asn Gly Lys Arg Ile Gly Ser 305 310 315 320 Glu Asp Glu Lys Leu Thr Gly Leu Pro Ser Lys Val Gln Asp Thr Val 325 330 335 Glu Glu Ser Ser Glu Ser Ile Leu Arg Lys Arg Ile Arg Glu Asp Arg 340 345 350 Lys Ala Thr Thr Ala Gln Lys Val Gln Gln Met Lys Gln Arg Leu Asn 355 360 365 Glu Thr Glu Arg Lys Arg Lys Arg Pro Arg Leu Thr Asp Thr 370 375 380 <210> SEQ ID NO 23 <211> LENGTH: 1494 <212> TYPE: DNA <213> ORGANISM: Rattus novegicus <400> SEQUENCE: 23 ttccgctcgc gctcccccgc cgccatgtcg gctaccatcg agcgggagtt cgaggaactg 60 gatgctcagt gtcgctggca gccgttatac ttggaaattc gaaatgaatc ccatgactat 120 cctcatagag tggccaagtt tccagaaaac agaaatcgaa acagatacag agatgtaagc 180 ccatatgatc acagtcgtgt taaactgcag agtgctgaaa atgattatat taatgccagc 240 ttagttgaca tagaagaggc acaaagaagt tacatcttaa cacagggccc acttcctaac 300 acgtgctgcc atttctggct catggtgtgg cagcaaaaga ccagagcagt tgtcatgcta 360 aaccgaactg tagagaaaga atcggttaaa tgtgcacagt actggccaac ggatgaccga 420 gagatggtgt ttaaggaaac aggattcagc gtgaagctct tatctgaaga tgtgaaatca 480 tattatacag tacatctact acagttagaa aatatcaata gtggtgaaac cagaaccata 540 tctcactttc attataccac ctggccagat tttggcgttc cggagtcacc agcttcattc 600 ctaaatttct tgtttaaagt tagagaatct ggttctttga accctgacca tgggcctgca 660 gtgatccatt gcagtgcagg catcgggcgt tctggcacct tctctcttgt agatacctgt 720 ctcgttctga tggagaaagg agaggatgtt aatgtgaaac aaatattact gagtatgaga 780 aagtatcgaa tgggactcat tcagactccg gaccagctca gattctccta catggccata 840 atagaaggag caaagtatac aaaaggagat tcaaatatac agaacagaac aatgactgag 900 aagtacaacg ggaagagaat agggtcagaa gatgaaaagt taacaggact ttcttctaag 960 gttccagata ctgtggaaga gagcagtgag agtattctcc ggaaacgcat tcgagaggat 1020 agaaaggcta caaccgctca gaaggtgcag cagatgagac agaggctaaa tgaaactgaa 1080 cggaaaagga aaaggccaag attgacagac acctaaatgt tcatgacttg agactattct 1140 gcagctataa attttgaacc tttgatgtgc aaagcaagac ctgaagccca ctccggaaac 1200 taaagtgagg cttgctaacc ctgtagattg cctcacaagt tgtctgttta caaagtaagc 1260 tttacatcca ggggatgaag aacgccacca gcagaagact tgcaaaccct ttaatttgac 1320 gtattgtttt ttaacatgtg tatgaattgt agaaagatgt aaagaaaata aaattaggag 1380 agactacttt gtattgtact gccattccta atgtattttt atactttttg gcagcattaa 1440 atatttttat taaatagaca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1494 <210> SEQ ID NO 24 <211> LENGTH: 363 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 24 Met Ser Ala Thr Ile Glu Arg Glu Phe Glu Glu Leu Asp Ala Gln Cys 1 5 10 15 Arg Trp Gln Pro Leu Tyr Leu Glu Ile Arg Asn Glu Ser His Asp Tyr 20 25 30 Pro His Arg Val Ala Lys Phe Pro Glu Asn Arg Asn Arg Asn Arg Tyr 35 40 45 Arg Asp Val Ser Pro Tyr Asp His Ser Arg Val Lys Leu Gln Ser Ala 50 55 60 Glu Asn Asp Tyr Ile Asn Ala Ser Leu Val Asp Ile Glu Glu Ala Gln 65 70 75 80 Arg Ser Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Cys His 85 90 95 Phe Trp Leu Met Val Trp Gln Gln Lys Thr Arg Ala Val Val Met Leu 100 105 110 Asn Arg Thr Val Glu Lys Glu Ser Val Lys Cys Ala Gln Tyr Trp Pro 115 120 125 Thr Asp Asp Arg Glu Met Val Phe Lys Glu Thr Gly Phe Ser Val Lys 130 135 140 Leu Leu Ser Glu Asp Val Lys Ser Tyr Tyr Thr Val His Leu Leu Gln 145 150 155 160 Leu Glu Asn Ile Asn Ser Gly Glu Thr Arg Thr Ile Ser His Phe His 165 170 175 Tyr Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser Phe 180 185 190 Leu Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Asn Pro Asp 195 200 205 His Gly Pro Ala Val Ile His Cys Ser Ala Gly Ile Gly Arg Ser Gly 210 215 220 Thr Phe Ser Leu Val Asp Thr Cys Leu Val Leu Met Glu Lys Gly Glu 225 230 235 240 Asp Val Asn Val Lys Gln Ile Leu Leu Ser Met Arg Lys Tyr Arg Met 245 250 255 Gly Leu Ile Gln Thr Pro Asp Gln Leu Arg Phe Ser Tyr Met Ala Ile 260 265 270 Ile Glu Gly Ala Lys Tyr Thr Lys Gly Asp Ser Asn Ile Gln Asn Arg 275 280 285 Thr Met Thr Glu Lys Tyr Asn Gly Lys Arg Ile Gly Ser Glu Asp Glu 290 295 300 Lys Leu Thr Gly Leu Ser Ser Lys Val Pro Asp Thr Val Glu Glu Ser 305 310 315 320 Ser Glu Ser Ile Leu Arg Lys Arg Ile Arg Glu Asp Arg Lys Ala Thr 325 330 335 Thr Ala Gln Lys Val Gln Gln Met Arg Gln Arg Leu Asn Glu Thr Glu 340 345 350 Arg Lys Arg Lys Arg Pro Arg Leu Thr Asp Thr 355 360 <210> SEQ ID NO 25 <211> LENGTH: 2543 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 cggccccagg cctggagggg ggtctgtgcg cggccggctg gctctgcccc gcgtccggtc 60 ccgagcgggc ctccctcggg ccagcccgat gtgaccgagc ccagcggagc ctgagcaagg 120 agcgggtccg tcgcggagcc ggagggcggg aggaacatga catcgcggag atggtttcac 180 ccaaatatca ctggtgtgga ggcagaaaac ctactgttga caagaggagt tgatggcagt 240 tttttggcaa ggcctagtaa aagtaaccct ggagacttca cactttccgt tagaagaaat 300 ggagctgtca cccacatcaa gattcagaac actggtgatt actatgacct gtatggaggg 360 gagaaatttg ccactttggc tgagttggtc cagtattaca tggaacatca cgggcaatta 420 aaagagaaga atggagatgt cattgagctt aaatatcctc tgaactgtgc agatcctacc 480 tctgaaaggt ggtttcatgg acatctctct gggaaagaag cagagaaatt attaactgaa 540 aaaggaaaac atggtagttt tcttgtacga gagagccaga gccaccctgg agattttgtt 600 ctttctgtgc gcactggtga tgacaaaggg gagagcaatg acggcaagtc taaagtgacc 660 catgttatga ttcgctgtca ggaactgaaa tacgacgttg gtggaggaga acggtttgat 720 tctttgacag atcttgtgga acattataag aagaatccta tggtggaaac attgggtaca 780 gtactacaac tcaagcagcc ccttaacacg actcgtataa atgctgctga aatagaaagc 840 agagttcgag aactaagcaa attagctgag accacagata aagtcaaaca aggcttttgg 900 gaagaatttg agacactaca acaacaggag tgcaaacttc tctacagccg aaaagagggt 960 caaaggcaag aaaacaaaaa caaaaataga tataaaaaca tcctgccctt tgatcatacc 1020 agggttgtcc tacacgatgg tgatcccaat gagcctgttt cagattacat caatgcaaat 1080 atcatcatgc ctgaatttga aaccaagtgc aacaattcaa agcccaaaaa gagttacatt 1140 gccacacaag gctgcctgca aaacacggtg aatgactttt ggcggatggt gttccaagaa 1200 aactcccgag tgattgtcat gacaacgaaa gaagtggaga gaggaaagag taaatgtgtc 1260 aaatactggc ctgatgagta tgctctaaaa gaatatggcg tcatgcgtgt taggaacgtc 1320 aaagaaagcg ccgctcatga ctatacgcta agagaactta aactttcaaa ggttggacaa 1380 gggaatacgg agagaacggt ctggcaatac cactttcgga cctggccgga ccacggcgtg 1440 cccagcgacc ctgggggcgt gctggacttc ctggaggagg tgcaccataa gcaggagagc 1500 atcatggatg cagggccggt cgtggtgcac tgcagtgctg gaattggccg gacagggacg 1560 ttcattgtga ttgatattct tattgacatc atcagagaga aaggtgttga ctgcgatatt 1620 gacgttccca aaaccatcca gatggtgcgg tctcagaggt cagggatggt ccagacagaa 1680 gcacagtacc gatttatcta tatggcggtc cagcattata ttgaaacact acagcgcagg 1740 attgaagaag agcagaaaag gaagaggaaa gggcacgaat atacaaatat taagtatcct 1800 ctagcggacc agacgagtgg agatcagagc cctctcccgc cttgtactcc aacgccaccc 1860 tgtgcagaaa tgagagaaga cagtgctaga gtctatgaaa acgtgggcct gatgcaacag 1920 cagaaaagtt tcagatgaga aaacctgcca aaacttcagc acagaaatag atgtggactt 1980 tcaccctctc cctaaaaaga tcaagaacag acgcaagaaa gtttatgtga agacagaatt 2040 tggatttgga aggcttgcaa tgtggttgac taccttttga taagcaaaat ttgaaaccat 2100 ttaaagacca ctgtatttta actcaacaat acctgcttcc caattactca tttcctcaga 2160 taagaagaaa tcatctctac aatgtagaca acattatatt ttatagaatt tgtttgaaat 2220 tgaggaagca gttaaattgt gcgctgtatt ttgcagatta tggggattca aattctagta 2280 ataggctttt ttatttttat ttttataccc ttaaccagtt taattttttt tttcctcatt 2340 gttggggatg atgagaagaa atgatttggg aaaattaagt aacaacgacc tagaaaagtg 2400 agaacaatct catttaccat catgtatcca gtagtggata attcattttg atggcttcta 2460 tttttggcca aatgagaata agccagtgcc tgagactgtc agaagttgac ctttgcactg 2520 gcattaaaga gtcatagaaa aaa 2543 <210> SEQ ID NO 26 <211> LENGTH: 593 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala 1 5 10 15 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn 35 40 45 Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr 65 70 75 80 Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile 85 90 95 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp 100 105 110 Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu 115 120 125 Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser 145 150 155 160 Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu 165 170 175 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp 180 185 190 Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr 195 200 205 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Ala 210 215 220 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Lys Leu Ala Glu Thr Thr 225 230 235 240 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Phe Glu Thr Leu Gln Gln 245 250 255 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Glu Gly Gln Arg Gln Glu 260 265 270 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Thr 275 280 285 Arg Val Val Leu His Asp Gly Asp Pro Asn Glu Pro Val Ser Asp Tyr 290 295 300 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Glu Thr Lys Cys Asn Asn 305 310 315 320 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gln Gly Cys Leu Gln Asn 325 330 335 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gln Glu Asn Ser Arg Val 340 345 350 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gly Lys Ser Lys Cys Val 355 360 365 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Glu Tyr Gly Val Met Arg 370 375 380 Val Arg Asn Val Lys Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 385 390 395 400 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Thr Glu Arg Thr Val Trp 405 410 415 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro 420 425 430 Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser 435 440 445 Ile Met Asp Ala Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly 450 455 460 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Leu Ile Asp Ile Ile Arg 465 470 475 480 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pro Lys Thr Ile Gln Met 485 490 495 Val Arg Ser Gln Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Arg 500 505 510 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Glu Thr Leu Gln Arg Arg 515 520 525 Ile Glu Glu Glu Gln Lys Arg Lys Arg Lys Gly His Glu Tyr Thr Asn 530 535 540 Ile Lys Tyr Pro Leu Ala Asp Gln Thr Ser Gly Asp Gln Ser Pro Leu 545 550 555 560 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Glu Met Arg Glu Asp Ser 565 570 575 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gln Gln Gln Lys Ser Phe 580 585 590 Arg <210> SEQ ID NO 27 <211> LENGTH: 2276 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 ctgccccgcg tccggtcccg agcgggcctc cctcgggcca gcccgatgtg accgagccca 60 gcggagcctg agcaaggagc gggtccgtcg cggagccgga gggcgggagg aacatgacat 120 cgcggagatg gtttcaccca aatatcactg gtgtggaggc agaaaaccta ctgttgacaa 180 gaggagttga tggcagtttt ttggcaaggc ctagtaaaag taaccctgga gacttcacac 240 tttccgttag aagaaatgga gctgtcaccc acatcaagat tcagaacact ggtgattact 300 atgacctgta tggaggggag aaatttgcca ctttggctga gttggtccag tattacatgg 360 aacatcacgg gcaattaaaa gagaagaatg gagatgtcat tgagcttaaa tatcctctga 420 actgtgcaga tcctacctct gaaaggtggt ttcatggaca tctctctggg aaagaagcag 480 agaaattatt aactgaaaaa ggaaaacatg gtagttttct tgtacgagag agccagagcc 540 accctggaga ttttgttctt tctgtgcgca ctggtgatga caaaggggag agcaatgacg 600 gcaagtctaa agtgacccat gttatgattc gctgtcagga actgaaatac gacgttggtg 660 gaggagaacg gtttgattct ttgacagatc ttgtggaaca ttataagaag aatcctatgg 720 tggaaacatt gggtacagta ctacaactca agcagcccct taacacgact cgtataaatg 780 ctgctgaaat agaaagcaga gttcgagaac taagcaaatt agctgagacc acagataaag 840 tcaaacaagg cttttgggaa gaatttgaga cactacaaca acaggagtgc aaacttctct 900 acagccgaaa agagggtcaa aggcaagaaa acaaaaacaa aaatagatat aaaaacatcc 960 tgccctttga tcataccagg gttgtcctac acgatggtga tcccaatgag cctgtttcag 1020 attacatcaa tgcaaatatc atcatgcctg aatttgaaac caagtgcaac aattcaaagc 1080 ccaaaaagag ttacattgcc acacaaggct gcctgcaaaa cacggtgaat gacttttggc 1140 ggatggtgtt ccaagaaaac tcccgagtga ttgtcatgac aacgaaagaa gtggagagag 1200 gaaagagtaa atgtgtcaaa tactggcctg atgagtatgc tctaaaagaa tatggcgtca 1260 tgcgtgttag gaacgtcaaa gaaagcgccg ctcatgacta tacgctaaga gaacttaaac 1320 tttcaaaggt tggacaaggg aatacggaga gaacggtctg gcaataccac tttcggacct 1380 ggccggacca cggcgtgccc agcgaccctg ggggcgtgct ggacttcctg gaggaggtgc 1440 accataagca ggagagcatc atggatgcag ggccggtcgt ggtgcactgc agtgctggaa 1500 ttggccggac agggacgttc attgtgattg atattcttat tgacatcatc agagagaaag 1560 gtgttgactg cgatattgac gttcccaaaa ccatccagat ggtgcggtct cagaggtcag 1620 ggatggtcca gacagaagca cagtaccgat ttatctatat ggcggtccag cattatattg 1680 aaacactaca gcgcaggatt gaagaagagc agaaaagcaa gaggaaaggg cacgaatata 1740 caaatattaa gtattctcta gcggaccaga cgagtggaga tcagagccct ctcccgcctt 1800 gtactccaac gccaccctgt gcagaaatga gagaagacag tgctagagtc tatgaaaacg 1860 tgggcctgat gcaacagcag aaaagtttca gatgagaaaa cctgccaaaa cttcagcaca 1920 gaaatagatg tggactttca ccctctccct aaaaagatca agaacagacg caagaaagtt 1980 tatgtgaaga cagaatttgg atttggaagg cttgcaatgt ggttgactac cttttgataa 2040 gcaaaatttg aaaccattta aagaccactg tattttaact caacaatacc tgcttcccaa 2100 ttactcattt cctcagataa gaagaaatca tctctacaat gtagacaaca ttatatttta 2160 tagaatttgt ttgaaattga ggaagcagtt aaattgtgcg ctgtattttg cagattatgg 2220 ggattcaaat tctagtaata ggctttttta tttttatttt tataccctta accagg 2276 <210> SEQ ID NO 28 <211> LENGTH: 593 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala 1 5 10 15 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn 35 40 45 Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr 65 70 75 80 Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile 85 90 95 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp 100 105 110 Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu 115 120 125 Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser 145 150 155 160 Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu 165 170 175 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp 180 185 190 Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr 195 200 205 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Ala 210 215 220 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Lys Leu Ala Glu Thr Thr 225 230 235 240 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Phe Glu Thr Leu Gln Gln 245 250 255 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Glu Gly Gln Arg Gln Glu 260 265 270 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Thr 275 280 285 Arg Val Val Leu His Asp Gly Asp Pro Asn Glu Pro Val Ser Asp Tyr 290 295 300 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Glu Thr Lys Cys Asn Asn 305 310 315 320 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gln Gly Cys Leu Gln Asn 325 330 335 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gln Glu Asn Ser Arg Val 340 345 350 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gly Lys Ser Lys Cys Val 355 360 365 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Glu Tyr Gly Val Met Arg 370 375 380 Val Arg Asn Val Lys Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 385 390 395 400 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Thr Glu Arg Thr Val Trp 405 410 415 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro 420 425 430 Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser 435 440 445 Ile Met Asp Ala Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly 450 455 460 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Leu Ile Asp Ile Ile Arg 465 470 475 480 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pro Lys Thr Ile Gln Met 485 490 495 Val Arg Ser Gln Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Arg 500 505 510 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Glu Thr Leu Gln Arg Arg 515 520 525 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gly His Glu Tyr Thr Asn 530 535 540 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gly Asp Gln Ser Pro Leu 545 550 555 560 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Glu Met Arg Glu Asp Ser 565 570 575 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gln Gln Gln Lys Ser Phe 580 585 590 Arg <210> SEQ ID NO 29 <211> LENGTH: 2121 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 cgccaggcct ggaggggggt ctgtgcgcgg ccggctggct ctgccccgcg tccggtcccg 60 agcgggcctc cctcgggcca gcccgatgtg accgagccca gcggagcctg agcaaggagc 120 gggtccgtcg cggagccgga gggcgggagg aacatgacat cgcggagatg gtttcaccca 180 aatatcactg gtgtggaggc agaaaaccta ctgttgacaa gaggagttga tggcagtttt 240 ttggcaaggc ctagtaaaag taaccctgga gacttcacac tttccgttag aagaaatgga 300 gctgtcaccc acatcaagat tcagaacact ggtgattact atgacctgta tggaggggag 360 aaatttgcca ctttggctga gttggtccag tattacatgg aacatcacgg gcaattaaaa 420 gagaagaatg gagatgtcat tgagcttaaa tatcctctga actgtgcaga tcctacctct 480 gaaaggtggt ttcatggaca tctctctggg aaagaagcag agaaattatt aactgaaaaa 540 ggaaaacatg gtagttttct tgtacgagag agccagagcc accctggaga ttttgttctt 600 tctgtgcgca ctggtgatga caaaggggag agcaatgacg gcaagtctaa agtgacccat 660 gttatgattc gctgtcagga actgaaatac gacgttggtg gaggagaacg gtttgattct 720 ttgacagatc ttgtggaaca ttataagaag aatcctatgg tggaaacatt gggtacagta 780 ctacaactca agcagcccct taacacgact cgtataaatg ctgctgaaat agaaagcaga 840 gttcgagaac taagcaaatt agctgagacc acagataaag tcaaacaagg cttttgggaa 900 gaatttgaga cactacaaca acaggagtgc aaacttctct acagccgaaa agagggtcaa 960 aggcaagaaa acaaaaacaa aaatagatat aaaaacatcc tgccctttga tcataccagg 1020 gttgtcctac acgatggtga tcccaatgag cctgtttcag attacatcaa tgcaaatatc 1080 atcatgcctg aatttgaaac caagtgcaac aattcaaagc ccaaaaagag ttacattgcc 1140 acacaaggct gcctgcaaaa cacggtgaat gacttttggc ggatggtgtt ccaagaaaac 1200 tcccgagtga ttgtcatgac aacgaaagaa gtggagagag gaaagagtaa atgtgtcaaa 1260 tactggcctg atgagtatgc tctaaaagaa tatggcgtca tgcgtgttag gaacgtcaaa 1320 gaaagcgccg ctcatgacta tacgctaaga gaacttaaac tttcaaaggt tggacaaggg 1380 aatacggaga gaacggtctg gcaataccac tttcggacct ggccggacca cggcgtgccc 1440 agcgaccctg ggggcgtgct ggacttcctg gaggaggtgc accataagca ggagagcatc 1500 atggatgcag ggccggtcgt ggtgcactgc agtgctggaa ttggccggac agggacgttc 1560 attgtgattg atattcttat tgacatcatc agagagaaag gtgttgactg cgatattgac 1620 gttcccaaaa ccatccagat ggtgcggtct cagaggtcag ggatggtcca gacagaagca 1680 cagtaccgat ttatctatat ggcggtccag cattatattg aaacactaca gcgcaggatt 1740 gaagaagagc agaaaagcaa gaggaaaggg cacgaatata caaatattaa gtattctcta 1800 gcggaccaga cgagtggaga tcagagccct ctcccgcctt gtactccaac gccaccctgt 1860 gcagaaatga gagaagacag tgctagagtc tatgaaaacg tgggcctgat gcaacagcag 1920 aaaagtttca gatgagaaaa cctgccaaaa cttcagcaca gaaatagatg tggactttca 1980 ccctctccct aaaaagatca agaacagacg caagaaagtt tatgtgaaga cagaatttgg 2040 atttggaagg cttgcaatgt ggttgactac cttttgataa gcaaaatttg aaaccattta 2100 aagaccactg tattttaact c 2121 <210> SEQ ID NO 30 <211> LENGTH: 593 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala 1 5 10 15 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn 35 40 45 Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr 65 70 75 80 Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile 85 90 95 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp 100 105 110 Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu 115 120 125 Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser 145 150 155 160 Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu 165 170 175 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp 180 185 190 Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr 195 200 205 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Ala 210 215 220 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Lys Leu Ala Glu Thr Thr 225 230 235 240 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Phe Glu Thr Leu Gln Gln 245 250 255 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Glu Gly Gln Arg Gln Glu 260 265 270 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Thr 275 280 285 Arg Val Val Leu His Asp Gly Asp Pro Asn Glu Pro Val Ser Asp Tyr 290 295 300 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Glu Thr Lys Cys Asn Asn 305 310 315 320 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gln Gly Cys Leu Gln Asn 325 330 335 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gln Glu Asn Ser Arg Val 340 345 350 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gly Lys Ser Lys Cys Val 355 360 365 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Glu Tyr Gly Val Met Arg 370 375 380 Val Arg Asn Val Lys Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 385 390 395 400 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Thr Glu Arg Thr Val Trp 405 410 415 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro 420 425 430 Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser 435 440 445 Ile Met Asp Ala Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly 450 455 460 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Leu Ile Asp Ile Ile Arg 465 470 475 480 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pro Lys Thr Ile Gln Met 485 490 495 Val Arg Ser Gln Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Arg 500 505 510 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Glu Thr Leu Gln Arg Arg 515 520 525 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gly His Glu Tyr Thr Asn 530 535 540 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gly Asp Gln Ser Pro Leu 545 550 555 560 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Glu Met Arg Glu Asp Ser 565 570 575 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gln Gln Gln Lys Ser Phe 580 585 590 Arg <210> SEQ ID NO 31 <211> LENGTH: 1980 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 ggcacgagcg gctggctctg cccgcgtccg gtcccgagcg ggcctccctc gggccagccc 60 gatgtgaccg agcccagcgg agcctgagca aggagcgggt ccgtcgcgga gccggagggc 120 gggaggaaca tgacatcgcg gagatggttt cacccaaata tcactggtgt ggaggcagaa 180 aacctactgt tgacaagagg agttgatggc agttttttgg caaggcctag taaaagtaac 240 cctggagact tcacactttc cgttagaaga aatggagctg tcacccacat caagattcag 300 aacactggtg attactatga cctgtatgga ggggagaaat ttgccacttt ggctgagttg 360 gtccagtatt acatggaaca tcacgggcaa ttaaaagaga agaatggaga tgtcattgag 420 cttaaatatc ctctgaactg tgcagatcct acctctgaaa ggtggtttca tggacatctc 480 tctgggaaag aagcagagaa attattaact gaaaaaggaa aacatggtag ttttcttgta 540 cgagagagcc agagccaccc tggagatttt gttctttctg tgcgcactgg tgatgacaaa 600 ggggagagca atgacggcaa gtctaaagtg acccatgtta tgattcgctg tcaggaactg 660 aaatacgacg ttggtggagg agaacggttt gattctttga cagatcttgt ggaacattat 720 aagaagaatc ctatggtgga aacattgggt acagtactac aactcaagca gccccttaac 780 acgactcgta taaatgctgc tgaaatagaa agcagagttc gagaactaag caaattagct 840 gagaccacag ataaagtcaa acaaggcttt tgggaagaat ttgagacact acaacaacag 900 gagtgcaaac ttctctacag ccgaaaagag ggtcaaaggc aagaaaacaa aaacaaaaat 960 agatataaaa acatcctgcc ctttgatcat accagggttg tcctacacga tggtgatccc 1020 aatgagcctg tttcagatta catcaatgca aatatcatca tgcctgaatt tgaaaccaag 1080 tgcaacaatt caaagcccaa aaagagttac attgccacac aaggctgcct gcaaaacacg 1140 gtgaatgact tttggcggat ggtgttccaa gaaaactccc gagtgattgt catgacaacg 1200 aaagaagtgg agagaggaaa gagtaaatgt gtcaaatact ggcctgatga gtatgctcta 1260 aaagaatatg gcgtcatgcg tgttaggaac gtcaaagaaa gcgccgctca tgactatacg 1320 ctaagagaac ttaaactttc aaaggttgga caagggaata cggagagaac ggtctggcaa 1380 taccactttc ggacctggcc ggaccacggc gtgcccagcg accctggggg cgtgctggac 1440 ttcctggagg aggtgcacca taagcaggag agcatcatgg atgcagggcc ggtcgtggtg 1500 cactgcagtg ctggaattgg ccggacaggg acgttcattg tgattgatat tcttattgac 1560 atcatcagag agaaaggtgt tgactgcgat attgacgttc ccaaaaccat ccagatggtg 1620 cggtctcaga ggtcagggat ggtccagaca gaagcacagt accgatttat ctatatggcg 1680 gtccagcatt atattgaaac actacagcgc aggattgaag aagagcagaa aagcaagagg 1740 aaagggcacg aatatacaaa tattaagtat tctctagcgg accagacgag tggagatcag 1800 agccctctcc cgccttgtac tccaacgcca ccctgtgcag aaatgagaga agacagtgct 1860 agagtctatg aaaacgtggg cctgatgcaa cagcagaaaa gtttcagatg agaaaacctg 1920 ccaaaacttc agcacagaaa tagatgtgga ctttcacctc tccctaaaaa gatcaggacc 1980 <210> SEQ ID NO 32 <211> LENGTH: 593 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala 1 5 10 15 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn 35 40 45 Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr 65 70 75 80 Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile 85 90 95 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp 100 105 110 Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu 115 120 125 Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser 145 150 155 160 Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu 165 170 175 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp 180 185 190 Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr 195 200 205 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Ala 210 215 220 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Lys Leu Ala Glu Thr Thr 225 230 235 240 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Phe Glu Thr Leu Gln Gln 245 250 255 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Glu Gly Gln Arg Gln Glu 260 265 270 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Thr 275 280 285 Arg Val Val Leu His Asp Gly Asp Pro Asn Glu Pro Val Ser Asp Tyr 290 295 300 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Glu Thr Lys Cys Asn Asn 305 310 315 320 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gln Gly Cys Leu Gln Asn 325 330 335 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gln Glu Asn Ser Arg Val 340 345 350 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gly Lys Ser Lys Cys Val 355 360 365 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Glu Tyr Gly Val Met Arg 370 375 380 Val Arg Asn Val Lys Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 385 390 395 400 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Thr Glu Arg Thr Val Trp 405 410 415 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro 420 425 430 Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser 435 440 445 Ile Met Asp Ala Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly 450 455 460 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Leu Ile Asp Ile Ile Arg 465 470 475 480 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pro Lys Thr Ile Gln Met 485 490 495 Val Arg Ser Gln Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Arg 500 505 510 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Glu Thr Leu Gln Arg Arg 515 520 525 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gly His Glu Tyr Thr Asn 530 535 540 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gly Asp Gln Ser Pro Leu 545 550 555 560 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Glu Met Arg Glu Asp Ser 565 570 575 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gln Gln Gln Lys Ser Phe 580 585 590 Arg <210> SEQ ID NO 33 <211> LENGTH: 2338 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 ggaggagcga gccgggccgg ggggcagctg cacagtctcc gggatcccca ggcctggagg 60 ggggtctgtg cgcggccggc tggctctgcc ccgcgtccgg tcccgagcgg gcctccctcg 120 ggccagcccg atgtgaccga gcccagcgga gcctgagcaa ggagcgggtc cgtcgcggag 180 ccggagggcg ggaggaacat gacatcgcgg agatggtttc acccaaatat cactggtgtg 240 gaggcagaaa acctactgtt gacaagagga gttgatggca gttttttggc aaggcctagt 300 aaaagtaacc ctggagactt cacactttcc gttagaagaa atggagctgt cacccacatc 360 aagattcaga acactggtga ttactatgac ctgtatggag gggagaaatt tgccactttg 420 gctgagttgg tccagtatta catggaacat cacgggcaat taaaagagaa gaatggagat 480 gtcattgagc ttaaatatcc tctgaactgt gcagatccta cctctgaaag gtggtttcat 540 ggacatctct ctgggaaaga agcagagaaa ttattaactg aaaaaggaaa acatggtagt 600 tttcttgtac gagagagcca gagccaccct ggagattttg ttctttctgt gcgcactggt 660 gatgacaaag gggagagcaa tgacggcaag tctaaagtga cccatgttat gattcgctgt 720 caggaactga aatacgacgt tggtggagga gaacggtttg attctttgac agatcttgtg 780 gaacattata agaagaatcc tatggtggaa acattgggta cagtactaca actcaagcag 840 ccccttaaca cgactcgtat aaatgctgct gaaatagaaa gcagagttcg agaactaagc 900 aaattagctg agaccacaga taaagtcaaa caaggctttt gggaagaatt tgagacacta 960 caacaacagg agtgcaaact tctctacagc cgaaaagagg gtcaaaggca agaaaacaaa 1020 aacaaaaata gatataaaaa catcctgccc tttgatcata ccagggttgt cctacacgat 1080 ggtgatccca atgagcctgt ttcagattac atcaatgcaa atatcatcat gcctgaattt 1140 gaaaccaagt gcaacaattc aaagcccaaa aagagttaca ttgccacaca aggctgcctg 1200 caaaacacgg tgaatgactt ttggcggatg gtgttccaag aaaactcccg agtgattgtc 1260 atgacaacga aagaagtgga gagaggaaag agtaaatgtg tcaaatactg gcctgatgag 1320 tatgctctaa aagaatatgg cgtcatgcgt gttaggaacg tcaaagaaag cgccgctcat 1380 gactatacgc taagagaact taaactttca aaggttggac aagggaatac ggagagaacg 1440 gtctggcaat accactttcg gacctggccg gaccacggcg tgcccagcga ccctgggggc 1500 gtgctggact tcctggagga ggtgcaccat aagcaggaga gcatcatgga tgcagggccg 1560 gtcgtggtgc actgcagtgc tggaattggc cggacaggga cgttcattgt gattgatatt 1620 cttattgaca tcatcagaga gaaaggtgtt gactgcgata ttgacgttcc caaaaccatc 1680 cagatggtgc ggtctcagag gtcagggatg gtccagacag aagcacagta ccgatttatc 1740 tatatggcgg tccagcatta tattgaaaca ctacagcgca ggattgaaga agagcagaaa 1800 agcaagagga aagggcacga atatacaaat attaagtatt ctctagcgga ccagacgagt 1860 ggagatcaga gccctctccc gccttgtact ccaacgccac cctgtgcaga aatgagagaa 1920 gacagtgcta gagtctatga aaacgtgggc ctgatgcaac agcagaaaag tttcagatga 1980 gaaaacctgc caaaacttca gcacagaaat agatgtggac tttcaccctc tccctaaaaa 2040 gatcaagaac agacgcaaga aagtttatgt gaagacagaa tttggatttg ggaaggcttg 2100 caatgtggtt gactaccttt tgataagcaa aatttgaaac catttaaaga ccactgtatt 2160 ttaactcaac aatacctgct tcccaattac tcatttcctc agataagaag aaatcatctc 2220 tacaatgtag acaacattat attttataga atttgtttga aattgaggaa gcagttaaat 2280 tgtgcgctgt attttgcaga ggattatggg gattcaaatt ctagtaatag gccttttt 2338 <210> SEQ ID NO 34 <211> LENGTH: 274 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 cagtactggc ctgatgagta tgctctaaaa gaatatggcg tcatgcgtgt taggaacgtc 60 aaagaaagcg ccgctcatga ctatacgcta agagaactta aactttcaaa ggttggacaa 120 gggaatacgg agagaacggt ctggcaatac cactttcgga cctggccgga ccacggcgtg 180 cccagcgacc ctgggggcgt gctggacttc ctggaggagg tgcaccataa gcaggagagc 240 atcatggatg cagggccggt cgtggtgcac tgca 274 <210> SEQ ID NO 35 <211> LENGTH: 91 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 Gln Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Glu Tyr Gly Val Met Arg 1 5 10 15 Val Arg Asn Val Lys Glu Ser Ala Ala His Asp Tyr Thr Leu Arg Glu 20 25 30 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Thr Glu Arg Thr Val Trp 35 40 45 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro 50 55 60 Gly Gly Val Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser 65 70 75 80 Ile Met Asp Ala Gly Pro Val Val Val His Cys 85 90 <210> SEQ ID NO 36 <211> LENGTH: 90 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 36 acggagagaa cggtctggca ataccacttt cggacctggc cggaccacgg cgtgcccagc 60 gaccctgggg gcgtgctgga cttcctggag 90 <210> SEQ ID NO 37 <211> LENGTH: 3984 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 37 ctgcaggtta ttcagcgata gttatgacct cccggttacg tgcgttgggt ggaagaatta 60 ataatatacg cacctcggag ttacccaaag agaaaactcg atcagaagtc atttgcagca 120 tccacttttt agatggcgtg gtacagacct ttaaagttac taaacaagac actggccagg 180 ttcttctgga tatggtgcac aaccacctgg gtgtgactga aaaggaatat tttggtttac 240 agcatgatga cgactccgtg gactctccta gatggctgga agcaagcaaa cccatcagga 300 agcagttaaa aggaggtttc ccctgtaccc tgcattttcg agtaagattt tttatacctg 360 atcccaacac actgcagcaa gaacaaacca ggcacttgta tttcttacaa ctgaagatgg 420 atatttgcga aggaaggtta acctgccctc ttaactcagc agtggttcta gcgtcctatg 480 ccgtacaatc tcattttgga gactataatt cttccataca tcatccaggc tatctttccg 540 atagtcactt tatacccgat caaaatgagg actttttaac aaaagtcgaa tctctgcatg 600 agcagcacag tgggctaaaa caatcagaag cagaatcctg ctatatcaac atagcgcgga 660 ccctcgactt ctatggagta gaactgcaca gtggtaggga tctgcacaat ttagacctaa 720 tgattggaat tgcttccgcg ggtgttgctg tgtaccgaaa atacatttgc acaagtttct 780 atccttgggt gaacattctc aaaatttctt tcaaaaggaa aaagttcttc atacatcagc 840 gacagaaaca ggctgaatcc agggaacata ttgtggcctt caacatgctg aattaccgat 900 cttgcaaaaa cttgtggaaa tcctgtgttg agcaccatac gttctttcag gcaaagaagc 960 tactacctca ggaaaagaat gttctgtctc agtactggac tatgggctct cggaacacca 1020 aaaagtcggt aaataaccaa tattgcaaaa aggtgattgg cgggatggtg tggaacccag 1080 ccatgcggag atccttatca gtggagcact tagaaaccaa gagtctgcct tctcgttccc 1140 ctcccattac tcccaactgg cgaagtcctc ggctccggca cgaaatccga aagccacgcc 1200 actcttctgc agataacctt gcaaatgaaa tgacctacat cacggaaacg gaagatgtat 1260 tttacacgta caagggctct ctggcccctc aagacagcga ttctgaagtt tctcagaacc 1320 gaagcccgca ccaagagagt ttatccgaga acaatccggc acaaagctac ctgacccaga 1380 agtcatccag ttctgtgtct ccatcttcaa atgctccagg ctcctgctca cctgacggcg 1440 ttgatcagca gctcttagat gacttccaca gggtgaccaa agggggctcc accgaggacg 1500 ccagccagta ctactgtgac aagaatgata atggtgacag ctacttagtc ttgatccgta 1560 tcacaccaga tgaagatgga aaatttggat ttaatcttaa gggaggagtg gatcaaaaga 1620 tgcctcttgt ggtatcaagg ataaacccag agtcacctgc ggacacctgc attcctaagc 1680 tgaacgaagg ggatcaaatc gtgttaatca atggccggga catctcagaa cacacgcatg 1740 accaagtggt gatgttcatc aaagccagcc gggagtccca ctcacgggag ctggccctgg 1800 tgatcaggag gagagctgtc cgctcatttg ctgacttcaa gtctgaagat gaactgaacc 1860 agcttttccc cgaagccatt ttccccatgt gtccggaggg tggggacact ttggagggat 1920 ccatggcaca gctaaagaag ggcctcgaaa gcgggacggt gctgatccag tttgagcaac 1980 tctacagaaa aaagccaggt ttggccatca cgtttgcaaa gctgcctcaa aatttggaca 2040 aaaaccgata taaagatgtg ctgccttatg acaccacccg ggtattattg cagggaaatg 2100 aagattatat taatgcaagt tacgtgaaca tggaaattcc tgctgctaac cttgtgaaca 2160 agtacatcgc cactcagggg cccctgccgc atacctgtgc acagttttgg caggttgtct 2220 gggatcagaa gttgtcactc attgtcatgt tgacgactct cacagaacga gggcggacca 2280 aatgtcacca gtactggcca gatccccccg acgtcatgaa ccacggcggc tttcacatcc 2340 agtgtcagtc agaggactgc accatcgcct atgtgtcccg agaaatgctg gtcacaaaca 2400 cccagaccgg ggaagaacac acagtgacac atctccagta cgtcgcatgg cctgaccacg 2460 gtatacccga tgactcctcc gactttctgg aatttgtaaa ctatgtgagg tctctgagag 2520 tggacagcga gcctgtccta gttcactgca gtgctggaat aggtcgaacc ggtgtgttgg 2580 tcactatgga aacagccatg tgcctaactg agaggaacct gcccatttac ccactggata 2640 ttgtccgaaa aatgcgagac cagcgcgcca tgatggtgca gacatcaagc cagtacaagt 2700 ttgtgtgtga agcgattctt cgtgtgtatg aagaaggttt agtccaaatg ctggatccta 2760 gttaagacaa ctgtgaaaaa gttcattcct ctttcccaag ggcatcctcc ttgaaagagg 2820 aggacagacc tctctggaag cagcaagagg aaccagtagc tgtgggaaag gaatgggcac 2880 ctctgaaccc aggcacttta aacttctata gaaaagatat cgtgtacata ggaactggtg 2940 tagataagca tgcaattatg gcatcattta ggcctgtatt tctatggaaa gatacaaaaa 3000 ggatctcagt ttggggcctg tcctaatgcc ttcttcccta acatcaccac acacacccct 3060 gtcggcatcc tggagcaatt gagaccggac acccacagag ctgttgtcct cccagcaaca 3120 agatggtgtg gttatcttgg gtcatttgga tgttttgttt gtttctgtgt gtcagactgt 3180 aagggctgag ctttctgtgc ttctaggtgg agctggaaca attcagattc acccgccctg 3240 atgctaagga aaccctgacg tatgtactag atggcagggc actgggggtc aggctgaagg 3300 ctgagcaaca cctctctgcc ctccctccct ttgtcccatc tcccagcgac ttccaatatt 3360 catgtttctg agaattgtgt ccctcttcag ttccctcttg gtgcctaacc tggattagta 3420 atgtgcattc aggtgaattt tcagctgagg ctctgagaac tggtactctc agtgtgttct 3480 ggtcatcttg tggcttagtt gtagaagcag gtgtgtctct tgcctctgct tgcctcctac 3540 tgcacactca gcacccagga ctggaatcac cgactactga atctcctaca tgtattgctg 3600 ctacttcaag ctcctccact tgaaacctta tgattttcca aggggagatg ggacagtgtc 3660 atctaaatat tccgaatgtt tggccttctg agaaaagagc ttctagtaat tgaaccatgg 3720 gtttcccagc ttctggaggg ttggccgtgg gctgtgtaca tgtgtgtgcc caggggtgag 3780 tgtttctcag gattcctaac gattcaaatt accgttgagt atatataaag aatcgagtct 3840 ctgtatggaa gaacaaatgt gtgcattcac ccccagtcac aatggtctcc attgcatttc 3900 aaaggagagg atcagactat ctgaatataa acacaatctg atgttaattt attctaagaa 3960 caccatcatt ttgattgtcc taaa 3984 <210> SEQ ID NO 38 <211> LENGTH: 913 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 Met Thr Ser Arg Leu Arg Ala Leu Gly Gly Arg Ile Asn Asn Ile Arg 1 5 10 15 Thr Ser Glu Leu Pro Lys Glu Lys Thr Arg Ser Glu Val Ile Cys Ser 20 25 30 Ile His Phe Leu Asp Gly Val Val Gln Thr Phe Lys Val Thr Lys Gln 35 40 45 Asp Thr Gly Gln Val Leu Leu Asp Met Val His Asn His Leu Gly Val 50 55 60 Thr Glu Lys Glu Tyr Phe Gly Leu Gln His Asp Asp Asp Ser Val Asp 65 70 75 80 Ser Pro Arg Trp Leu Glu Ala Ser Lys Pro Ile Arg Lys Gln Leu Lys 85 90 95 Gly Gly Phe Pro Cys Thr Leu His Phe Arg Val Arg Phe Phe Ile Pro 100 105 110 Asp Pro Asn Thr Leu Gln Gln Glu Gln Thr Arg His Leu Tyr Phe Leu 115 120 125 Gln Leu Lys Met Asp Ile Cys Glu Gly Arg Leu Thr Cys Pro Leu Asn 130 135 140 Ser Ala Val Val Leu Ala Ser Tyr Ala Val Gln Ser His Phe Gly Asp 145 150 155 160 Tyr Asn Ser Ser Ile His His Pro Gly Tyr Leu Ser Asp Ser His Phe 165 170 175 Ile Pro Asp Gln Asn Glu Asp Phe Leu Thr Lys Val Glu Ser Leu His 180 185 190 Glu Gln His Ser Gly Leu Lys Gln Ser Glu Ala Glu Ser Cys Tyr Ile 195 200 205 Asn Ile Ala Arg Thr Leu Asp Phe Tyr Gly Val Glu Leu His Ser Gly 210 215 220 Arg Asp Leu His Asn Leu Asp Leu Met Ile Gly Ile Ala Ser Ala Gly 225 230 235 240 Val Ala Val Tyr Arg Lys Tyr Ile Cys Thr Ser Phe Tyr Pro Trp Val 245 250 255 Asn Ile Leu Lys Ile Ser Phe Lys Arg Lys Lys Phe Phe Ile His Gln 260 265 270 Arg Gln Lys Gln Ala Glu Ser Arg Glu His Ile Val Ala Phe Asn Met 275 280 285 Leu Asn Tyr Arg Ser Cys Lys Asn Leu Trp Lys Ser Cys Val Glu His 290 295 300 His Thr Phe Phe Gln Ala Lys Lys Leu Leu Pro Gln Glu Lys Asn Val 305 310 315 320 Leu Ser Gln Tyr Trp Thr Met Gly Ser Arg Asn Thr Lys Lys Ser Val 325 330 335 Asn Asn Gln Tyr Cys Lys Lys Val Ile Gly Gly Met Val Trp Asn Pro 340 345 350 Ala Met Arg Arg Ser Leu Ser Val Glu His Leu Glu Thr Lys Ser Leu 355 360 365 Pro Ser Arg Ser Pro Pro Ile Thr Pro Asn Trp Arg Ser Pro Arg Leu 370 375 380 Arg His Glu Ile Arg Lys Pro Arg His Ser Ser Ala Asp Asn Leu Ala 385 390 395 400 Asn Glu Met Thr Tyr Ile Thr Glu Thr Glu Asp Val Phe Tyr Thr Tyr 405 410 415 Lys Gly Ser Leu Ala Pro Gln Asp Ser Asp Ser Glu Val Ser Gln Asn 420 425 430 Arg Ser Pro His Gln Glu Ser Leu Ser Glu Asn Asn Pro Ala Gln Ser 435 440 445 Tyr Leu Thr Gln Lys Ser Ser Ser Ser Val Ser Pro Ser Ser Asn Ala 450 455 460 Pro Gly Ser Cys Ser Pro Asp Gly Val Asp Gln Gln Leu Leu Asp Asp 465 470 475 480 Phe His Arg Val Thr Lys Gly Gly Ser Thr Glu Asp Ala Ser Gln Tyr 485 490 495 Tyr Cys Asp Lys Asn Asp Asn Gly Asp Ser Tyr Leu Val Leu Ile Arg 500 505 510 Ile Thr Pro Asp Glu Asp Gly Lys Phe Gly Phe Asn Leu Lys Gly Gly 515 520 525 Val Asp Gln Lys Met Pro Leu Val Val Ser Arg Ile Asn Pro Glu Ser 530 535 540 Pro Ala Asp Thr Cys Ile Pro Lys Leu Asn Glu Gly Asp Gln Ile Val 545 550 555 560 Leu Ile Asn Gly Arg Asp Ile Ser Glu His Thr His Asp Gln Val Val 565 570 575 Met Phe Ile Lys Ala Ser Arg Glu Ser His Ser Arg Glu Leu Ala Leu 580 585 590 Val Ile Arg Arg Arg Ala Val Arg Ser Phe Ala Asp Phe Lys Ser Glu 595 600 605 Asp Glu Leu Asn Gln Leu Phe Pro Glu Ala Ile Phe Pro Met Cys Pro 610 615 620 Glu Gly Gly Asp Thr Leu Glu Gly Ser Met Ala Gln Leu Lys Lys Gly 625 630 635 640 Leu Glu Ser Gly Thr Val Leu Ile Gln Phe Glu Gln Leu Tyr Arg Lys 645 650 655 Lys Pro Gly Leu Ala Ile Thr Phe Ala Lys Leu Pro Gln Asn Leu Asp 660 665 670 Lys Asn Arg Tyr Lys Asp Val Leu Pro Tyr Asp Thr Thr Arg Val Leu 675 680 685 Leu Gln Gly Asn Glu Asp Tyr Ile Asn Ala Ser Tyr Val Asn Met Glu 690 695 700 Ile Pro Ala Ala Asn Leu Val Asn Lys Tyr Ile Ala Thr Gln Gly Pro 705 710 715 720 Leu Pro His Thr Cys Ala Gln Phe Trp Gln Val Val Trp Asp Gln Lys 725 730 735 Leu Ser Leu Ile Val Met Leu Thr Thr Leu Thr Glu Arg Gly Arg Thr 740 745 750 Lys Cys His Gln Tyr Trp Pro Asp Pro Pro Asp Val Met Asn His Gly 755 760 765 Gly Phe His Ile Gln Cys Gln Ser Glu Asp Cys Thr Ile Ala Tyr Val 770 775 780 Ser Arg Glu Met Leu Val Thr Asn Thr Gln Thr Gly Glu Glu His Thr 785 790 795 800 Val Thr His Leu Gln Tyr Val Ala Trp Pro Asp His Gly Ile Pro Asp 805 810 815 Asp Ser Ser Asp Phe Leu Glu Phe Val Asn Tyr Val Arg Ser Leu Arg 820 825 830 Val Asp Ser Glu Pro Val Leu Val His Cys Ser Ala Gly Ile Gly Arg 835 840 845 Thr Gly Val Leu Val Thr Met Glu Thr Ala Met Cys Leu Thr Glu Arg 850 855 860 Asn Leu Pro Ile Tyr Pro Leu Asp Ile Val Arg Lys Met Arg Asp Gln 865 870 875 880 Arg Ala Met Met Val Gln Thr Ser Ser Gln Tyr Lys Phe Val Cys Glu 885 890 895 Ala Ile Leu Arg Val Tyr Glu Glu Gly Leu Val Gln Met Leu Asp Pro 900 905 910 Ser <210> SEQ ID NO 39 <211> LENGTH: 2111 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 agcagcacag tgggctaaaa caatcagaag cagaatcctg ctatatcaac atagcgcgga 60 ccctcgactt ctatggagta gaactgcaca gtggtaggga tctgcacaat ttagacctaa 120 tgattggaat tgcttccgcg ggtgttgctg tgtaccgaaa atacatttgc acaagtttct 180 atccttgggt gaacattctc aaaatttctt tcaaaaggaa aaagttcttc atacatcagc 240 gacagaaaca ggctgaatcc agggaacata ttgtggcctt caacatgctg aattaccgat 300 cttgcaaaaa cttgtggaaa tcctgtgttg agcaccatac gttctttcag gcaaagaagc 360 tactacctca ggaaaagaat gttctgtctc agtactggac tatgggctct cggaacacca 420 aaaagtcggt aaataaccaa tattgcaaaa aggtgattgg cgggatggtg tggaacccag 480 ccatgcggag atccttatca gtggagcact tagaaaccaa gagtctgcct tctcgttccc 540 ctcccattac tcccaactgg cgaagtcctc ggctccggca cgaaatccga aagccacgcc 600 actcttctgc agataacctt gcaaatgaaa tgacctacat cacggaaacg gaagatgtat 660 tttacacgta caagggctct ctggcccctc aagacagcga ttctgaagtt tctcagaacc 720 gaagcccgca ccaagagagt ttatccgaga acaatccggc acaaagctac ctgacccaga 780 agtcatccag ttctgtgtct ccatcttcaa atgctccagg ctcctgctca cctgacggcg 840 ttgatcagca gctcttagat gacttccaca gggtgaccaa agggggctcc accgaggacg 900 ccagccagta ctactgtgac aagaatgata atggtgacag ctacttagtc ttgatccgta 960 tcacaccaga tgaagatgga aaatttggat ttaatcttaa gggaggagtg gatcaaaaga 1020 tgcctcttgt ggtatcaagg ataaacccag agtcacctgc ggacacctgc attcctaagc 1080 tgaacgaagg ggatcaaatc gtgttaatca atggccggga catctcagaa cacacgcatg 1140 accaagtggt gatgttcatc aaagccagcc gggagtccca ctcacgggag ctggccctgg 1200 tgatcaggag gagagctgtc cgctcatttg ctgacttcaa gtctgaagat gaactgaacc 1260 agcttttccc cgaagccatt ttccccatgt gtccggaggg tggggacact ttggagggat 1320 ccatggcaca gctaaagaag ggcctcgaaa gcgggacggt gctgatccag tttgagcaac 1380 tctacagaaa aaagccaggt ttggccatca cgtttgcaaa gctgcctcaa aatttggaca 1440 aaaaccgata taaagatgtg ctgccttatg acaccacccg ggtattattg cagggaaatg 1500 aagattatat taatgcaagt tacgtgaaca tggaaattcc tgctgctaac cttgtgaaca 1560 agtacatcgc cactcagggg cccctgccgc atacctgtgc acagttttgg caggttgtct 1620 gggatcagaa gttgtcactc attgtcatgt tgacgactct cacagaacga gggcggacca 1680 aatgtcacca gtactggcca gatccccccg acgtcatgaa ccacggcggc tttcacatcc 1740 agtgtcagtc agaggactgc accatcgcct atgtgtcccg agaaatgctg gtcacaaaca 1800 cccagaccgg ggaagaacac acagtgacac atctccagta cgtcgcatgg cctgaccacg 1860 gtatacccga tgactcctcc gactttctgg aatttgtaaa ctatgtgagg tctctgagag 1920 tggacagcga gcctgtccta gttcactgca gtgctggaat aggtcgaacc ggtgtgttgg 1980 tcactatgga aacagccatg tgcctaactg agaggaacct gcccatttac ccactggata 2040 ttgtccgaaa aatgcgagac cagcgcgcca tgatggtgca gacatcaagc cagtacaagt 2100 ttgtgtgtga a 2111 <210> SEQ ID NO 40 <211> LENGTH: 703 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 Gln His Ser Gly Leu Lys Gln Ser Glu Ala Glu Ser Cys Tyr Ile Asn 1 5 10 15 Ile Ala Arg Thr Leu Asp Phe Tyr Gly Val Glu Leu His Ser Gly Arg 20 25 30 Asp Leu His Asn Leu Asp Leu Met Ile Gly Ile Ala Ser Ala Gly Val 35 40 45 Ala Val Tyr Arg Lys Tyr Ile Cys Thr Ser Phe Tyr Pro Trp Val Asn 50 55 60 Ile Leu Lys Ile Ser Phe Lys Arg Lys Lys Phe Phe Ile His Gln Arg 65 70 75 80 Gln Lys Gln Ala Glu Ser Arg Glu His Ile Val Ala Phe Asn Met Leu 85 90 95 Asn Tyr Arg Ser Cys Lys Asn Leu Trp Lys Ser Cys Val Glu His His 100 105 110 Thr Phe Phe Gln Ala Lys Lys Leu Leu Pro Gln Glu Lys Asn Val Leu 115 120 125 Ser Gln Tyr Trp Thr Met Gly Ser Arg Asn Thr Lys Lys Ser Val Asn 130 135 140 Asn Gln Tyr Cys Lys Lys Val Ile Gly Gly Met Val Trp Asn Pro Ala 145 150 155 160 Met Arg Arg Ser Leu Ser Val Glu His Leu Glu Thr Lys Ser Leu Pro 165 170 175 Ser Arg Ser Pro Pro Ile Thr Pro Asn Trp Arg Ser Pro Arg Leu Arg 180 185 190 His Glu Ile Arg Lys Pro Arg His Ser Ser Ala Asp Asn Leu Ala Asn 195 200 205 Glu Met Thr Tyr Ile Thr Glu Thr Glu Asp Val Phe Tyr Thr Tyr Lys 210 215 220 Gly Ser Leu Ala Pro Gln Asp Ser Asp Ser Glu Val Ser Gln Asn Arg 225 230 235 240 Ser Pro His Gln Glu Ser Leu Ser Glu Asn Asn Pro Ala Gln Ser Tyr 245 250 255 Leu Thr Gln Lys Ser Ser Ser Ser Val Ser Pro Ser Ser Asn Ala Pro 260 265 270 Gly Ser Cys Ser Pro Asp Gly Val Asp Gln Gln Leu Leu Asp Asp Phe 275 280 285 His Arg Val Thr Lys Gly Gly Ser Thr Glu Asp Ala Ser Gln Tyr Tyr 290 295 300 Cys Asp Lys Asn Asp Asn Gly Asp Ser Tyr Leu Val Leu Ile Arg Ile 305 310 315 320 Thr Pro Asp Glu Asp Gly Lys Phe Gly Phe Asn Leu Lys Gly Gly Val 325 330 335 Asp Gln Lys Met Pro Leu Val Val Ser Arg Ile Asn Pro Glu Ser Pro 340 345 350 Ala Asp Thr Cys Ile Pro Lys Leu Asn Glu Gly Asp Gln Ile Val Leu 355 360 365 Ile Asn Gly Arg Asp Ile Ser Glu His Thr His Asp Gln Val Val Met 370 375 380 Phe Ile Lys Ala Ser Arg Glu Ser His Ser Arg Glu Leu Ala Leu Val 385 390 395 400 Ile Arg Arg Arg Ala Val Arg Ser Phe Ala Asp Phe Lys Ser Glu Asp 405 410 415 Glu Leu Asn Gln Leu Phe Pro Glu Ala Ile Phe Pro Met Cys Pro Glu 420 425 430 Gly Gly Asp Thr Leu Glu Gly Ser Met Ala Gln Leu Lys Lys Gly Leu 435 440 445 Glu Ser Gly Thr Val Leu Ile Gln Phe Glu Gln Leu Tyr Arg Lys Lys 450 455 460 Pro Gly Leu Ala Ile Thr Phe Ala Lys Leu Pro Gln Asn Leu Asp Lys 465 470 475 480 Asn Arg Tyr Lys Asp Val Leu Pro Tyr Asp Thr Thr Arg Val Leu Leu 485 490 495 Gln Gly Asn Glu Asp Tyr Ile Asn Ala Ser Tyr Val Asn Met Glu Ile 500 505 510 Pro Ala Ala Asn Leu Val Asn Lys Tyr Ile Ala Thr Gln Gly Pro Leu 515 520 525 Pro His Thr Cys Ala Gln Phe Trp Gln Val Val Trp Asp Gln Lys Leu 530 535 540 Ser Leu Ile Val Met Leu Thr Thr Leu Thr Glu Arg Gly Arg Thr Lys 545 550 555 560 Cys His Gln Tyr Trp Pro Asp Pro Pro Asp Val Met Asn His Gly Gly 565 570 575 Phe His Ile Gln Cys Gln Ser Glu Asp Cys Thr Ile Ala Tyr Val Ser 580 585 590 Arg Glu Met Leu Val Thr Asn Thr Gln Thr Gly Glu Glu His Thr Val 595 600 605 Thr His Leu Gln Tyr Val Ala Trp Pro Asp His Gly Ile Pro Asp Asp 610 615 620 Ser Ser Asp Phe Leu Glu Phe Val Asn Tyr Val Arg Ser Leu Arg Val 625 630 635 640 Asp Ser Glu Pro Val Leu Val His Cys Ser Ala Gly Ile Gly Arg Thr 645 650 655 Gly Val Leu Val Thr Met Glu Thr Ala Met Cys Leu Thr Glu Arg Asn 660 665 670 Leu Pro Ile Tyr Pro Leu Asp Ile Val Arg Lys Met Arg Asp Gln Arg 675 680 685 Ala Met Met Val Gln Thr Ser Ser Gln Tyr Lys Phe Val Cys Glu 690 695 700 <210> SEQ ID NO 41 <211> LENGTH: 5117 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 41 ccccagccgc atgacgcgcg gaggaggcag cgggacgagc gcgggagccg ggaccgggta 60 gccgcgcgct gggggtgggc gccgctcgct ccgccccgcg aagcccctgc gcgctcaggg 120 acgcggcccc cccgcggcag ccgcgctagg ctccggcgtg tggccgcggc cgccgccgcg 180 ctgccatgtc tccgggcaag ccggggcggg cggagcgggg acgaggcgga ccggctggcg 240 gaggaggagg cgaaggagac ggcaggaggc ggcgacgacg gtgcccgggc tcgggcgcac 300 ggcggggccc gattcgcgcg tccggggcac gttccagggc gcgcggggca tgaagccggc 360 ggcgcgggag gcgcggctgc ctccgcgctc gcccgggctg cgctgggcgc tgccgctgct 420 gctgctgctg ctgcgcctgg gccagatcct gtgcgcaggt ggcaccccta gtccaattcc 480 tgacccttca gtagcaactg ttgccacagg ggaaaatggc ataacgcaga tcagcagtac 540 agcagaatcc tttcataaac agaatggaac tggaacacct caggtggaaa caaacaccag 600 tgaggatggt gaaagctctg gagccaacga tagtttaaga acacctgaac aaggatctaa 660 tgggactgat ggggcatctc aaaaaactcc cagtagcact gggcccagtc ctgtgtttga 720 cattaaagct gtttccatca gtccaaccaa tgtgatctta acttggaaaa gtaatgacac 780 agctgcttct gagtacaagt atgtagtaaa gcataagatg gaaaatgaga agacaattac 840 tgttgtgcat caaccatggt gtaacatcac aggcttacgt ccagcgactt catatgtatt 900 ctccatcact ccaggaatag gcaatgagac ttggggagat cccagagtca taaaagtcat 960 cacagagccg atcccagttt ctgatctccg tgttgccctc acgggtgtga ggaaggctgc 1020 tctctcctgg agcaatggca atggcaccgc ctcctgccgg gttcttcttg aaagcattgg 1080 aagccatgag gagttgactc aagactcaag acttcaggtc aatatctcgg acctgaagcc 1140 aggggttcaa tacaacatca acccgtatct tctacaatca aataagacaa agggagaccc 1200 cttgggcaca gaaggtggct tggatgccag caatacagag agaagccggg cagggagccc 1260 caccgcccct gtgcatgatg agtccctcgt gggacctgtg gacccatcct ccggccagca 1320 gtcccgagac acggaagtcc tgcttgtcgg gttagagcct ggcacccgat acaatgccac 1380 cgtttattcc caagcagcga atggcacaga aggacagccc caggccatag agttcaggac 1440 aaatgctatt caggtttttg acgtcaccgc tgtgaacatc agtgccacaa gcctgaccct 1500 gatctggaaa gtcagcgata acgagtcgtc atctaactat acctacaaga tacatgtggc 1560 gggggagaca gattcttcca atctcaacgt cagtgagcct cgcgctgtca tccccggact 1620 ccgctccagc accttctaca acatcacagt gtgtcctgtc ctaggtgaca tcgagggcac 1680 gccgggcttc ctccaagtgc acaccccccc tgttccagtt tctgacttcc gagtgacagt 1740 ggtcagcacg acggagatcg gcttagcatg gagcagccat gatgcagaat catttcagat 1800 gcatatcaca caggagggag ctggcaattc tcgggtagaa ataaccacca accaaagtat 1860 tatcattggt ggcttgttcc ctggaaccaa gtattgcttt gaaatagttc caaaaggacc 1920 aaatgggact gaaggggcat ctcggacagt ttgcaataga actgttccca gtgcagtgtt 1980 tgacatccac gtggtctacg tcaccaccac ggagatgtgg ctggactgga agagccctga 2040 cggtgcttcc gagtatgtct accatttagt catagagtcc aagcatggct ctaaccacac 2100 aagcacgtat gacaaagcga ttactctcca gggcctgatt ccgggcacct tatataacat 2160 caccatctct ccagaagtgg accacgtctg gggggacccc aactccactg cacagtacac 2220 acggcccagc aatgtgtcca acattgatgt aagtaccaac accacagcag caactttaag 2280 ttggcagaac tttgatgacg cctctcccac gtactcctac tgccttctta ttgagaaggc 2340 tggaaattcc agcaacgcaa cacaagtagt cacggacatt ggaattactg acgctacagt 2400 cactgaatta atacctggct catcatacac agtggagatc tttgcacaag taggggatgg 2460 gatcaagtca ctggaacctg gccggaagtc attctgtaca gatcctgcgt ccatggcctc 2520 cttcgactgc gaagtggtcc ccaaagagcc agccctggtt ctcaaatgga cctgccctcc 2580 tggcgccaat gcaggctttg agctggaggt cagcagtgga gcctggaaca atgcgaccca 2640 cctggagagc tgctcctctg agaatggcac tgagtataga acggaagtca cgtatttgaa 2700 tttttctacc tcgtacaaca tcagcatcac cactgtgtcc tgtggaaaga tggcagcccc 2760 cacccggaac acctgcacta ctggcatcac agatccccct cctccagatg gatcccctaa 2820 tattacatct gtcagtcaca attcagtaaa ggtcaagttc agtggatttg aagccagcca 2880 cggacccatc aaagcctatg ctgtcattct caccaccggg gaagctggtc acccttctgc 2940 agatgtcctg aaatacacgt atgacgattt caaaaaggga gcctcagata cttatgtgac 3000 atacctcata agaacagaag aaaagggacg ttctcagagc ttgtctgaag ttttgaaata 3060 tgaaattgac gttgggaatg agtcaaccac acttggttat tacaatggga agctggaacc 3120 tctgggctcc taccgggctt gtgtggctgg cttcaccaac attaccttcc accctcaaaa 3180 caaggggctc attgatgggg ctgagagcta tgtgtccttc agtcgctact cagatgctgt 3240 ttccttgccc caggatccag gtgtcatctg tggagcggtt tttggctgta tctttggtgc 3300 cctggttatt gtgactgtgg gaggcttcat cttctggaga aagaagagga aagatgcaaa 3360 gaataatgaa gtgtcctttt ctcaaattaa acctaaaaaa tctaagttaa tcagagtgga 3420 gaattttgag gcctacttca agaagcagca agctgactcc aactgtgggt tcgcagagga 3480 atacgaagat ctgaagcttg ttggaattag tcaacctaaa tatgcagcag aactggctga 3540 gaatagagga aagaatcgct ataataatgt tctgccctat gatatttccc gtgtcaaact 3600 ttcggtccag acccattcaa cggatgacta catcaatgcc aactacatgc ctggctacca 3660 ctccaagaaa gattttattg ccacacaagg acctttaccg aacactttga aagatttttg 3720 gcgtatggtt tgggagaaaa atgtatatgc catcattatg ttgactaaat gtgttgaaca 3780 gggaagaacc aaatgtgagg agtattggcc ctccaagcag gctcaggact atggagacat 3840 aactgtggca atgacatcag aaattgttct tccggaatgg accatcagag atttcacagt 3900 gaaaaatatc cagacaagtg agagtcaccc tctgagacag ttccatttca cctcctggcc 3960 agaccacggt gttcccgaca ccactgacct gctcatcaac ttccggtacc tcgttcgtga 4020 ctacatgaag cagagtcctc ccgaatcgcc gattctggtg cattgcagtg ctggggtcgg 4080 aaggacgggc actttcattg ccattgatcg tctcatctac cagatagaga atgagaacac 4140 cgtggatgtg tatgggattg tgtatgacct tcgaatgcat aggcctttaa tggtgcagac 4200 agaggaccag tatgttttcc tcaatcagtg tgttttggat attgtcagat cccagaaaga 4260 ctcaaaagta gatcttatct accagaacac aactgcaatg acaatctatg aaaaccttgc 4320 gcccgtgacc acatttggaa agaccaatgg ttacatcgcc taattccaaa ggaataacct 4380 ttctggagtg aaccagaccg tcgcacccac agcgaaggca catgccccga tgtcgacatg 4440 tttttatatg tctaatatct taattctttg ttctgttttg tgagaactaa ttttgagggc 4500 atgaagctgc atatgataga tgacaaattg gggctgtcgg gggctgtgga tgggtgggga 4560 gcaaatcatc tgcattcctg atgaccaatg ggatgaggtc actttttttt ttttccccct 4620 tgaggattgc ggaaaaccag gaaaagggat ctatgatttt tttttccaaa acaatttctt 4680 ttttaaaaag actattttat atgattcaca tgctaaagcc aggattgtgt tgggttgaat 4740 atattttaag tatcagaggt ctatttttac ctactgtgtc ttggaatcta gccgatggaa 4800 aatacctaat tgtggatgat gattgcgcag ggaggggtac gtggcacctc ttccgaatgg 4860 gttttctatt tgaacatgtg ccttttctga attatgcttc cacaggcaaa actcagtaga 4920 gatctatatt tttgtactga atctcataat tggaatatac ggaatattta aacagtagct 4980 tagcatcaga ggtttgcttc ctcagtaaca tttctgttct catttgatca ggggaggcct 5040 ctttgccccg gccccgcttc ccctgccccc gtgtgatttg tgctccattt tttcttccct 5100 tttccctccc agttttc 5117 <210> SEQ ID NO 42 <211> LENGTH: 1337 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 42 Met Lys Pro Ala Ala Arg Glu Ala Arg Leu Pro Pro Arg Ser Pro Gly 1 5 10 15 Leu Arg Trp Ala Leu Pro Leu Leu Leu Leu Leu Leu Arg Leu Gly Gln 20 25 30 Ile Leu Cys Ala Gly Gly Thr Pro Ser Pro Ile Pro Asp Pro Ser Val 35 40 45 Ala Thr Val Ala Thr Gly Glu Asn Gly Ile Thr Gln Ile Ser Ser Thr 50 55 60 Ala Glu Ser Phe His Lys Gln Asn Gly Thr Gly Thr Pro Gln Val Glu 65 70 75 80 Thr Asn Thr Ser Glu Asp Gly Glu Ser Ser Gly Ala Asn Asp Ser Leu 85 90 95 Arg Thr Pro Glu Gln Gly Ser Asn Gly Thr Asp Gly Ala Ser Gln Lys 100 105 110 Thr Pro Ser Ser Thr Gly Pro Ser Pro Val Phe Asp Ile Lys Ala Val 115 120 125 Ser Ile Ser Pro Thr Asn Val Ile Leu Thr Trp Lys Ser Asn Asp Thr 130 135 140 Ala Ala Ser Glu Tyr Lys Tyr Val Val Lys His Lys Met Glu Asn Glu 145 150 155 160 Lys Thr Ile Thr Val Val His Gln Pro Trp Cys Asn Ile Thr Gly Leu 165 170 175 Arg Pro Ala Thr Ser Tyr Val Phe Ser Ile Thr Pro Gly Ile Gly Asn 180 185 190 Glu Thr Trp Gly Asp Pro Arg Val Ile Lys Val Ile Thr Glu Pro Ile 195 200 205 Pro Val Ser Asp Leu Arg Val Ala Leu Thr Gly Val Arg Lys Ala Ala 210 215 220 Leu Ser Trp Ser Asn Gly Asn Gly Thr Ala Ser Cys Arg Val Leu Leu 225 230 235 240 Glu Ser Ile Gly Ser His Glu Glu Leu Thr Gln Asp Ser Arg Leu Gln 245 250 255 Val Asn Ile Ser Asp Leu Lys Pro Gly Val Gln Tyr Asn Ile Asn Pro 260 265 270 Tyr Leu Leu Gln Ser Asn Lys Thr Lys Gly Asp Pro Leu Gly Thr Glu 275 280 285 Gly Gly Leu Asp Ala Ser Asn Thr Glu Arg Ser Arg Ala Gly Ser Pro 290 295 300 Thr Ala Pro Val His Asp Glu Ser Leu Val Gly Pro Val Asp Pro Ser 305 310 315 320 Ser Gly Gln Gln Ser Arg Asp Thr Glu Val Leu Leu Val Gly Leu Glu 325 330 335 Pro Gly Thr Arg Tyr Asn Ala Thr Val Tyr Ser Gln Ala Ala Asn Gly 340 345 350 Thr Glu Gly Gln Pro Gln Ala Ile Glu Phe Arg Thr Asn Ala Ile Gln 355 360 365 Val Phe Asp Val Thr Ala Val Asn Ile Ser Ala Thr Ser Leu Thr Leu 370 375 380 Ile Trp Lys Val Ser Asp Asn Glu Ser Ser Ser Asn Tyr Thr Tyr Lys 385 390 395 400 Ile His Val Ala Gly Glu Thr Asp Ser Ser Asn Leu Asn Val Ser Glu 405 410 415 Pro Arg Ala Val Ile Pro Gly Leu Arg Ser Ser Thr Phe Tyr Asn Ile 420 425 430 Thr Val Cys Pro Val Leu Gly Asp Ile Glu Gly Thr Pro Gly Phe Leu 435 440 445 Gln Val His Thr Pro Pro Val Pro Val Ser Asp Phe Arg Val Thr Val 450 455 460 Val Ser Thr Thr Glu Ile Gly Leu Ala Trp Ser Ser His Asp Ala Glu 465 470 475 480 Ser Phe Gln Met His Ile Thr Gln Glu Gly Ala Gly Asn Ser Arg Val 485 490 495 Glu Ile Thr Thr Asn Gln Ser Ile Ile Ile Gly Gly Leu Phe Pro Gly 500 505 510 Thr Lys Tyr Cys Phe Glu Ile Val Pro Lys Gly Pro Asn Gly Thr Glu 515 520 525 Gly Ala Ser Arg Thr Val Cys Asn Arg Thr Val Pro Ser Ala Val Phe 530 535 540 Asp Ile His Val Val Tyr Val Thr Thr Thr Glu Met Trp Leu Asp Trp 545 550 555 560 Lys Ser Pro Asp Gly Ala Ser Glu Tyr Val Tyr His Leu Val Ile Glu 565 570 575 Ser Lys His Gly Ser Asn His Thr Ser Thr Tyr Asp Lys Ala Ile Thr 580 585 590 Leu Gln Gly Leu Ile Pro Gly Thr Leu Tyr Asn Ile Thr Ile Ser Pro 595 600 605 Glu Val Asp His Val Trp Gly Asp Pro Asn Ser Thr Ala Gln Tyr Thr 610 615 620 Arg Pro Ser Asn Val Ser Asn Ile Asp Val Ser Thr Asn Thr Thr Ala 625 630 635 640 Ala Thr Leu Ser Trp Gln Asn Phe Asp Asp Ala Ser Pro Thr Tyr Ser 645 650 655 Tyr Cys Leu Leu Ile Glu Lys Ala Gly Asn Ser Ser Asn Ala Thr Gln 660 665 670 Val Val Thr Asp Ile Gly Ile Thr Asp Ala Thr Val Thr Glu Leu Ile 675 680 685 Pro Gly Ser Ser Tyr Thr Val Glu Ile Phe Ala Gln Val Gly Asp Gly 690 695 700 Ile Lys Ser Leu Glu Pro Gly Arg Lys Ser Phe Cys Thr Asp Pro Ala 705 710 715 720 Ser Met Ala Ser Phe Asp Cys Glu Val Val Pro Lys Glu Pro Ala Leu 725 730 735 Val Leu Lys Trp Thr Cys Pro Pro Gly Ala Asn Ala Gly Phe Glu Leu 740 745 750 Glu Val Ser Ser Gly Ala Trp Asn Asn Ala Thr His Leu Glu Ser Cys 755 760 765 Ser Ser Glu Asn Gly Thr Glu Tyr Arg Thr Glu Val Thr Tyr Leu Asn 770 775 780 Phe Ser Thr Ser Tyr Asn Ile Ser Ile Thr Thr Val Ser Cys Gly Lys 785 790 795 800 Met Ala Ala Pro Thr Arg Asn Thr Cys Thr Thr Gly Ile Thr Asp Pro 805 810 815 Pro Pro Pro Asp Gly Ser Pro Asn Ile Thr Ser Val Ser His Asn Ser 820 825 830 Val Lys Val Lys Phe Ser Gly Phe Glu Ala Ser His Gly Pro Ile Lys 835 840 845 Ala Tyr Ala Val Ile Leu Thr Thr Gly Glu Ala Gly His Pro Ser Ala 850 855 860 Asp Val Leu Lys Tyr Thr Tyr Asp Asp Phe Lys Lys Gly Ala Ser Asp 865 870 875 880 Thr Tyr Val Thr Tyr Leu Ile Arg Thr Glu Glu Lys Gly Arg Ser Gln 885 890 895 Ser Leu Ser Glu Val Leu Lys Tyr Glu Ile Asp Val Gly Asn Glu Ser 900 905 910 Thr Thr Leu Gly Tyr Tyr Asn Gly Lys Leu Glu Pro Leu Gly Ser Tyr 915 920 925 Arg Ala Cys Val Ala Gly Phe Thr Asn Ile Thr Phe His Pro Gln Asn 930 935 940 Lys Gly Leu Ile Asp Gly Ala Glu Ser Tyr Val Ser Phe Ser Arg Tyr 945 950 955 960 Ser Asp Ala Val Ser Leu Pro Gln Asp Pro Gly Val Ile Cys Gly Ala 965 970 975 Val Phe Gly Cys Ile Phe Gly Ala Leu Val Ile Val Thr Val Gly Gly 980 985 990 Phe Ile Phe Trp Arg Lys Lys Arg Lys Asp Ala Lys Asn Asn Glu Val 995 1000 1005 Ser Phe Ser Gln Ile Lys Pro Lys Lys Ser Lys Leu Ile Arg Val Glu 1010 1015 1020 Asn Phe Glu Ala Tyr Phe Lys Lys Gln Gln Ala Asp Ser Asn Cys Gly 1025 1030 1035 1040 Phe Ala Glu Glu Tyr Glu Asp Leu Lys Leu Val Gly Ile Ser Gln Pro 1045 1050 1055 Lys Tyr Ala Ala Glu Leu Ala Glu Asn Arg Gly Lys Asn Arg Tyr Asn 1060 1065 1070 Asn Val Leu Pro Tyr Asp Ile Ser Arg Val Lys Leu Ser Val Gln Thr 1075 1080 1085 His Ser Thr Asp Asp Tyr Ile Asn Ala Asn Tyr Met Pro Gly Tyr His 1090 1095 1100 Ser Lys Lys Asp Phe Ile Ala Thr Gln Gly Pro Leu Pro Asn Thr Leu 1105 1110 1115 1120 Lys Asp Phe Trp Arg Met Val Trp Glu Lys Asn Val Tyr Ala Ile Ile 1125 1130 1135 Met Leu Thr Lys Cys Val Glu Gln Gly Arg Thr Lys Cys Glu Glu Tyr 1140 1145 1150 Trp Pro Ser Lys Gln Ala Gln Asp Tyr Gly Asp Ile Thr Val Ala Met 1155 1160 1165 Thr Ser Glu Ile Val Leu Pro Glu Trp Thr Ile Arg Asp Phe Thr Val 1170 1175 1180 Lys Asn Ile Gln Thr Ser Glu Ser His Pro Leu Arg Gln Phe His Phe 1185 1190 1195 1200 Thr Ser Trp Pro Asp His Gly Val Pro Asp Thr Thr Asp Leu Leu Ile 1205 1210 1215 Asn Phe Arg Tyr Leu Val Arg Asp Tyr Met Lys Gln Ser Pro Pro Glu 1220 1225 1230 Ser Pro Ile Leu Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr 1235 1240 1245 Phe Ile Ala Ile Asp Arg Leu Ile Tyr Gln Ile Glu Asn Glu Asn Thr 1250 1255 1260 Val Asp Val Tyr Gly Ile Val Tyr Asp Leu Arg Met His Arg Pro Leu 1265 1270 1275 1280 Met Val Gln Thr Glu Asp Gln Tyr Val Phe Leu Asn Gln Cys Val Leu 1285 1290 1295 Asp Ile Val Arg Ser Gln Lys Asp Ser Lys Val Asp Leu Ile Tyr Gln 1300 1305 1310 Asn Thr Thr Ala Met Thr Ile Tyr Glu Asn Leu Ala Pro Val Thr Thr 1315 1320 1325 Phe Gly Lys Thr Asn Gly Tyr Ile Ala 1330 1335 <210> SEQ ID NO 43 <211> LENGTH: 4756 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 43 gcatgacgcg cggaggaggc agcgggagca gccgcgggag ccgggaccgg gtagccgcgc 60 gctgggggtg ggcgccgctc gctccgcccc gcgaagcccc tgcgcgctca gggacgcggc 120 ccccccgcgg cagccgcgct aggctccggc gtgtggccgc ggccgccgcc gccgctgcca 180 tgtctccggg gaagcccggg gcgggcggag cggggacgag gcggaccggc tggcggagga 240 ggaggcgaag gagacggcag gaggcggcga cgacggtgcc cgggctcggg cgcacggcgg 300 ggcccgattc gcgcgtccgg ggcacgttcc agggcgcgcg gggcatgaag ccggcggcgc 360 gggaggcgcg gctgcctccg cgctcgcccg ggctgcgctg ggcgctgccg ctgctgctgc 420 tgctgctgcg cctgggccag atcctgtgcg caggtggcac ccctagtcca attcctgacc 480 cttcagtagc aactgttgcc acaggggaaa atggcataac gcagatcagc agtacagcag 540 aatcctttca taaacagaat ggaactggaa cacctcaggt ggaaacaaac accagtgagg 600 atggtgaaag ctctggagcc aacgatagtt taagaacacc tgaacaagga tctaatggga 660 ctgatggggc atctcaaaaa actcccagta gcactgggcc cagtcctgtg tttgacatta 720 aagctgtttc catcagtcca accaatgtga tcttaacttg gaaaagtaat gacacagctg 780 cttctgagta caagtatgta gtaaagcata agatggaaaa tgagaagaca attactgttg 840 tgcatcaacc atggtgtaac atcacaggct tacgtccagc gacttcatat gtattctcca 900 tcactccagg aataggcaat gagacttggg gagatcccag agtcataaaa gtcatcacag 960 aaccgatccc agtttctgat ctccgtgttg ccctcacggg tgtgaggaag gctgctctct 1020 cctggagcaa tggcaatggc actgcctcct gccgggttct tcttgaaagc attggaagcc 1080 atgaggagtt gactcaagac tcaagacttc aggtcaatat ctcgggcctg aagccagggg 1140 ttcaatacaa catcaacccg tatcttctac aatcaaataa gacaaaggga gaccccttgg 1200 gcacagaagg tggcttggat gccagcaata cagagagaag ccgggcaggg agccccaccg 1260 cccctgtgca tgatgagtcc ctcgtgggac ctgtggaccc atcctccggc cagcagtccc 1320 gagacacgga agtcctgctt gtcgggttag agcctggcac ccgatacaat gccaccgttt 1380 attcccaagc agcgaatggc acagaaggac agccccaggc catagagttc aggacaaatg 1440 ctattcaggt ttttgacgtc accgctgtga acatcagtgc cacaagcctg accctgatct 1500 ggaaagtcag cgataacgag tcgtcatcta actataccta caagatacat gtggcggggg 1560 agacagattc ttccaatctc aacgtcagtg agcctcgcgc tgtcatcccc ggactccgct 1620 ccagcacctt ctacaacatc acagtgtgtc ctgtcctagg tgacatcgag ggcacgccgg 1680 gcttcctcca agtgcacacc ccccctgttc cagtttctga cttccgagtg acagtggtca 1740 gcacgacgga gatcggctta gcatggagca gccatgatgc agaatcattt cagatgcata 1800 tcacacagga gggagctggc aattctcggg tagaaataac caccaaccaa agtattatca 1860 ttggtggctt gttccctgga accaagtatt gctttgaaat agttccaaaa ggaccaaatg 1920 ggactgaagg ggcatctcgg acagtttgca atagaactgt tcccagtgca gtgtttgaca 1980 tccacgtggt ctacgtcacc accacggaga tgtggctgga ctggaagagc cctgacggtg 2040 cttccgagta tgtctaccat ttagtcatag agtccaagca tggctctaac cacacaagca 2100 cgtatgacaa agcgattact ctccagggcc tgattccggg caccttatat aacatcacca 2160 tctctccaga agtggaccac gtctgggggg accccaactc cactgcacag tacacacggc 2220 ccagcaatgt gtccaacatt gatgtaagta ccaacaccac agcagcaact ttaagttggc 2280 agaactttga tgacgcctct cccacgtact cctactgcct tcttattgag aaggctggaa 2340 attccagcaa cgcaacacaa gtagtcacgg acattggaat tactgacgct acagtcactg 2400 aattaatacc tggctcatca tacacagtgg agatctttgc acaagtaggg gatgggatca 2460 agtcactgga acctggccgg aagtcattct gtacagatcc tgcgtccatg gcctccttcg 2520 actgcgaagt ggtccccaaa gagccagccc tggttctcaa atggacctgc cctcctggcg 2580 ccaatgcagg ctttgagctg gaggtcagca gtggagcctg gaacaatgcg acccacctgg 2640 agagctgctc ctctgagaat ggcactgagt atagaacgga agtcacgtat ttgaattttt 2700 ctacctcgta caacatcagc atcaccactg tgtcctgtgg aaagatggca gcccccaccc 2760 ggaacacctg cactactggc atcacagatc cccctcctcc agatggatcc cctaatatta 2820 catctgtcag tcacaattca gtaaaggtca agttcagtgg atttgaagcc agccacggac 2880 ccatcaaagc ctatgctgtc attctcacca ccggggaagc tggtcaccct tctgcagatg 2940 tcctgaaata cacgtatgac gatttcaaaa agggagcctc agatacttat gtgacatacc 3000 tcataagaac agaagaaaag ggacgttctc agagcttgtc tgaagttttg aaatatgaaa 3060 ttgacgttgg gaatgagtca accacacttg gttatttaca atgggaagct ggaacctctg 3120 ggctcctacc ggcttgtgtg gctggcttca ccaacattac cttccaccct caaaacaagg 3180 ggctcattga tggggctgag agctatgtgt ccttcagtcg ctactcagat gctgtttcct 3240 tgccccagga tccaggtgtc atctgtggag cggtttttgg ctgtatcttt ggtgccctgg 3300 ttattgtgac tgtgggaggc ttcatcttct ggagaaagaa gaggaaagat gcaaagaata 3360 atgaagtgtc cttttctcaa attaaaccta aaaaatctaa gttaatcaga gtggagaatt 3420 ttgaggccta cttcaagaag cagcaagctg actccaactg tgggttcgca gaggaatacg 3480 aagatctgaa gcttgttgga attagtcaac ctaaatatgc agcagaactg gctgagaata 3540 gaggaaagaa tcgctataat aatgttctgc cctatgatat ttcccgtgtc aaactttcgg 3600 tccagaccca ttcaacggat gactacatca atgccaacta catgcctggc taccactcca 3660 agaaagattt tattgccaca caaggacctt taccgaacac tttgaaagat ttttggcgta 3720 tggtttggga gaaaaatgta tatgccatca ttatgttgac taaatgtgtt gaacagggaa 3780 gaaccaaatg tgaggagtat tggccctcca agcaggctca ggactatgga gacataactg 3840 tggcaatgac atcagaaatt gttcttccgg aatggaccat cagagatttc acagtgaaaa 3900 atatccagac aagtgagagt caccctctga gacagttcca tttcacctcc tggccagacc 3960 acggtgttcc cgacaccact gacctgctca tcaacttccg gtacctcgtt cgtgactaca 4020 tgaagcagag tcctcccgaa tcgccgattc tggtgcattg cagtgctggg gtcggaagga 4080 cgggcacttt cattgccatt gatcgtctca tctaccagat agagaatgag aacaccgtgg 4140 atgtgtatgg gattgtgtat gaccttcgaa tgcataggcc tttaatggtg cagacagagg 4200 accagtatgt tttcctcaat cagtgtgttt tggatattgt cagatcccag aaagactcaa 4260 aagtagatct tatctaccag aacacaactg caatgacaat ctatgaaaac cttgcgcccg 4320 tgaccacatt tggaaagacc aatggttaca tcgcctaatt ccaaaggaat aacctttctg 4380 gagtgaacca gaccgtcgca cccacagcga aggcacatgc ccgatgtcga catgttttat 4440 atgctaatat cttaattctt tgttctgttt tgtgagaact aattttgagg gcatgaagct 4500 gcatatcata gatgacaaat tggggctgtc gggggctgtg gatgggtggg gagcaaatca 4560 tctgcattcc tgatgaccaa tgggatgagg tcactttttt tttttttccc ccttcgaagg 4620 attgtggaaa accaggaaaa gggagctatg attttttttt ccaaaacaat ttctttttta 4680 aaaaagacta tttatatgat tcacatgcta aagccaggat tgtgttgggt tgaatatatt 4740 ttaagtatca gaggtc 4756 <210> SEQ ID NO 44 <211> LENGTH: 1337 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 44 Met Lys Pro Ala Ala Arg Glu Ala Arg Leu Pro Pro Arg Ser Pro Gly 1 5 10 15 Leu Arg Trp Ala Leu Pro Leu Leu Leu Leu Leu Leu Arg Leu Gly Gln 20 25 30 Ile Leu Cys Ala Gly Gly Thr Pro Ser Pro Ile Pro Asp Pro Ser Val 35 40 45 Ala Thr Val Ala Thr Gly Glu Asn Gly Ile Thr Gln Ile Ser Ser Thr 50 55 60 Ala Glu Ser Phe His Lys Gln Asn Gly Thr Gly Thr Pro Gln Val Glu 65 70 75 80 Thr Asn Thr Ser Glu Asp Gly Glu Ser Ser Gly Ala Asn Asp Ser Leu 85 90 95 Arg Thr Pro Glu Gln Gly Ser Asn Gly Thr Asp Gly Ala Ser Gln Lys 100 105 110 Thr Pro Ser Ser Thr Gly Pro Ser Pro Val Phe Asp Ile Lys Ala Val 115 120 125 Ser Ile Ser Pro Thr Asn Val Ile Leu Thr Trp Lys Ser Asn Asp Thr 130 135 140 Ala Ala Ser Glu Tyr Lys Tyr Val Val Lys His Lys Met Glu Asn Glu 145 150 155 160 Lys Thr Ile Thr Val Val His Gln Pro Trp Cys Asn Ile Thr Gly Leu 165 170 175 Arg Pro Ala Thr Ser Tyr Val Phe Ser Ile Thr Pro Gly Ile Gly Asn 180 185 190 Glu Thr Trp Gly Asp Pro Arg Val Ile Lys Val Ile Thr Glu Pro Ile 195 200 205 Pro Val Ser Asp Leu Arg Val Ala Leu Thr Gly Val Arg Lys Ala Ala 210 215 220 Leu Ser Trp Ser Asn Gly Asn Gly Thr Ala Ser Cys Arg Val Leu Leu 225 230 235 240 Glu Ser Ile Gly Ser His Glu Glu Leu Thr Gln Asp Ser Arg Leu Gln 245 250 255 Val Asn Ile Ser Gly Leu Lys Pro Gly Val Gln Tyr Asn Ile Asn Pro 260 265 270 Tyr Leu Leu Gln Ser Asn Lys Thr Lys Gly Asp Pro Leu Gly Thr Glu 275 280 285 Gly Gly Leu Asp Ala Ser Asn Thr Glu Arg Ser Arg Ala Gly Ser Pro 290 295 300 Thr Ala Pro Val His Asp Glu Ser Leu Val Gly Pro Val Asp Pro Ser 305 310 315 320 Ser Gly Gln Gln Ser Arg Asp Thr Glu Val Leu Leu Val Gly Leu Glu 325 330 335 Pro Gly Thr Arg Tyr Asn Ala Thr Val Tyr Ser Gln Ala Ala Asn Gly 340 345 350 Thr Glu Gly Gln Pro Gln Ala Ile Glu Phe Arg Thr Asn Ala Ile Gln 355 360 365 Val Phe Asp Val Thr Ala Val Asn Ile Ser Ala Thr Ser Leu Thr Leu 370 375 380 Ile Trp Lys Val Ser Asp Asn Glu Ser Ser Ser Asn Tyr Thr Tyr Lys 385 390 395 400 Ile His Val Ala Gly Glu Thr Asp Ser Ser Asn Leu Asn Val Ser Glu 405 410 415 Pro Arg Ala Val Ile Pro Gly Leu Arg Ser Ser Thr Phe Tyr Asn Ile 420 425 430 Thr Val Cys Pro Val Leu Gly Asp Ile Glu Gly Thr Pro Gly Phe Leu 435 440 445 Gln Val His Thr Pro Pro Val Pro Val Ser Asp Phe Arg Val Thr Val 450 455 460 Val Ser Thr Thr Glu Ile Gly Leu Ala Trp Ser Ser His Asp Ala Glu 465 470 475 480 Ser Phe Gln Met His Ile Thr Gln Glu Gly Ala Gly Asn Ser Arg Val 485 490 495 Glu Ile Thr Thr Asn Gln Ser Ile Ile Ile Gly Gly Leu Phe Pro Gly 500 505 510 Thr Lys Tyr Cys Phe Glu Ile Val Pro Lys Gly Pro Asn Gly Thr Glu 515 520 525 Gly Ala Ser Arg Thr Val Cys Asn Arg Thr Val Pro Ser Ala Val Phe 530 535 540 Asp Ile His Val Val Tyr Val Thr Thr Thr Glu Met Trp Leu Asp Trp 545 550 555 560 Lys Ser Pro Asp Gly Ala Ser Glu Tyr Val Tyr His Leu Val Ile Glu 565 570 575 Ser Lys His Gly Ser Asn His Thr Ser Thr Tyr Asp Lys Ala Ile Thr 580 585 590 Leu Gln Gly Leu Ile Pro Gly Thr Leu Tyr Asn Ile Thr Ile Ser Pro 595 600 605 Glu Val Asp His Val Trp Gly Asp Pro Asn Ser Thr Ala Gln Tyr Thr 610 615 620 Arg Pro Ser Asn Val Ser Asn Ile Asp Val Ser Thr Asn Thr Thr Ala 625 630 635 640 Ala Thr Leu Ser Trp Gln Asn Phe Asp Asp Ala Ser Pro Thr Tyr Ser 645 650 655 Tyr Cys Leu Leu Ile Glu Lys Ala Gly Asn Ser Ser Asn Ala Thr Gln 660 665 670 Val Val Thr Asp Ile Gly Ile Thr Asp Ala Thr Val Thr Glu Leu Ile 675 680 685 Pro Gly Ser Ser Tyr Thr Val Glu Ile Phe Ala Gln Val Gly Asp Gly 690 695 700 Ile Lys Ser Leu Glu Pro Gly Arg Lys Ser Phe Cys Thr Asp Pro Ala 705 710 715 720 Ser Met Ala Ser Phe Asp Cys Glu Val Val Pro Lys Glu Pro Ala Leu 725 730 735 Val Leu Lys Trp Thr Cys Pro Pro Gly Ala Asn Ala Gly Phe Glu Leu 740 745 750 Glu Val Ser Ser Gly Ala Trp Asn Asn Ala Thr His Leu Glu Ser Cys 755 760 765 Ser Ser Glu Asn Gly Thr Glu Tyr Arg Thr Glu Val Thr Tyr Leu Asn 770 775 780 Phe Ser Thr Ser Tyr Asn Ile Ser Ile Thr Thr Val Ser Cys Gly Lys 785 790 795 800 Met Ala Ala Pro Thr Arg Asn Thr Cys Thr Thr Gly Ile Thr Asp Pro 805 810 815 Pro Pro Pro Asp Gly Ser Pro Asn Ile Thr Ser Val Ser His Asn Ser 820 825 830 Val Lys Val Lys Phe Ser Gly Phe Glu Ala Ser His Gly Pro Ile Lys 835 840 845 Ala Tyr Ala Val Ile Leu Thr Thr Gly Glu Ala Gly His Pro Ser Ala 850 855 860 Asp Val Leu Lys Tyr Thr Tyr Asp Asp Phe Lys Lys Gly Ala Ser Asp 865 870 875 880 Thr Tyr Val Thr Tyr Leu Ile Arg Thr Glu Glu Lys Gly Arg Ser Gln 885 890 895 Ser Leu Ser Glu Val Leu Lys Tyr Glu Ile Asp Val Gly Asn Glu Ser 900 905 910 Thr Thr Leu Gly Tyr Leu Gln Trp Glu Ala Gly Thr Ser Gly Leu Leu 915 920 925 Pro Ala Cys Val Ala Gly Phe Thr Asn Ile Thr Phe His Pro Gln Asn 930 935 940 Lys Gly Leu Ile Asp Gly Ala Glu Ser Tyr Val Ser Phe Ser Arg Tyr 945 950 955 960 Ser Asp Ala Val Ser Leu Pro Gln Asp Pro Gly Val Ile Cys Gly Ala 965 970 975 Val Phe Gly Cys Ile Phe Gly Ala Leu Val Ile Val Thr Val Gly Gly 980 985 990 Phe Ile Phe Trp Arg Lys Lys Arg Lys Asp Ala Lys Asn Asn Glu Val 995 1000 1005 Ser Phe Ser Gln Ile Lys Pro Lys Lys Ser Lys Leu Ile Arg Val Glu 1010 1015 1020 Asn Phe Glu Ala Tyr Phe Lys Lys Gln Gln Ala Asp Ser Asn Cys Gly 1025 1030 1035 1040 Phe Ala Glu Glu Tyr Glu Asp Leu Lys Leu Val Gly Ile Ser Gln Pro 1045 1050 1055 Lys Tyr Ala Ala Glu Leu Ala Glu Asn Arg Gly Lys Asn Arg Tyr Asn 1060 1065 1070 Asn Val Leu Pro Tyr Asp Ile Ser Arg Val Lys Leu Ser Val Gln Thr 1075 1080 1085 His Ser Thr Asp Asp Tyr Ile Asn Ala Asn Tyr Met Pro Gly Tyr His 1090 1095 1100 Ser Lys Lys Asp Phe Ile Ala Thr Gln Gly Pro Leu Pro Asn Thr Leu 1105 1110 1115 1120 Lys Asp Phe Trp Arg Met Val Trp Glu Lys Asn Val Tyr Ala Ile Ile 1125 1130 1135 Met Leu Thr Lys Cys Val Glu Gln Gly Arg Thr Lys Cys Glu Glu Tyr 1140 1145 1150 Trp Pro Ser Lys Gln Ala Gln Asp Tyr Gly Asp Ile Thr Val Ala Met 1155 1160 1165 Thr Ser Glu Ile Val Leu Pro Glu Trp Thr Ile Arg Asp Phe Thr Val 1170 1175 1180 Lys Asn Ile Gln Thr Ser Glu Ser His Pro Leu Arg Gln Phe His Phe 1185 1190 1195 1200 Thr Ser Trp Pro Asp His Gly Val Pro Asp Thr Thr Asp Leu Leu Ile 1205 1210 1215 Asn Phe Arg Tyr Leu Val Arg Asp Tyr Met Lys Gln Ser Pro Pro Glu 1220 1225 1230 Ser Pro Ile Leu Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr 1235 1240 1245 Phe Ile Ala Ile Asp Arg Leu Ile Tyr Gln Ile Glu Asn Glu Asn Thr 1250 1255 1260 Val Asp Val Tyr Gly Ile Val Tyr Asp Leu Arg Met His Arg Pro Leu 1265 1270 1275 1280 Met Val Gln Thr Glu Asp Gln Tyr Val Phe Leu Asn Gln Cys Val Leu 1285 1290 1295 Asp Ile Val Arg Ser Gln Lys Asp Ser Lys Val Asp Leu Ile Tyr Gln 1300 1305 1310 Asn Thr Thr Ala Met Thr Ile Tyr Glu Asn Leu Ala Pro Val Thr Thr 1315 1320 1325 Phe Gly Lys Thr Asn Gly Tyr Ile Ala 1330 1335 <210> SEQ ID NO 45 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 45 Trp Arg Met Val Trp Glu Gln Asn Val Tyr Ala Ile Ile Met Leu Thr 1 5 10 15 Lys Cys Val Glu Gln Gly Arg Thr Lys Cys Glu Glu Tyr Trp Pro Ser 20 25 30 Lys Gln Ala Gln Asp Tyr Gly Asp Ile Thr Val Ala Met Thr Ser Glu 35 40 45 Ile Val Leu Pro Glu Trp Thr Ile Arg Asp Phe Thr Val Lys Asn Ile 50 55 60 Gln Thr Ser Glu Ser His Pro Leu Arg Gln Phe His Phe Thr Ser Trp 65 70 75 80 Pro Asp His Gly Val Pro Asp Thr Thr Asp Leu Leu Ile Asn Phe Arg 85 90 95 Tyr Leu Val Arg Asp Tyr Met Lys Gln Ser Pro Pro Glu Ser Glu Ile 100 105 110 Leu Val His Cys Ser Ala Gly Ile Gly Arg 115 120 <210> SEQ ID NO 46 <211> LENGTH: 4426 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 46 ccgttgctgt cgccgttgct gtcggacgcg cggaggaggc agagggagca gccggggccg 60 cgggagccgg gagctgggag ccacgcgcgg agggtgggcg ccgctcgctc cgccccgcga 120 agccctgcga gtctaaggcc gcggccgctc cgcgccaggc gcgctaggct ccgcgtgtgg 180 ccgccgccgc cgctgccatg tccccgggga agcccggggc gggcgacggg ggactaggcg 240 gaccggctgg cggagaagga ggcggaggcg tcggctggag acggagacga gggcgcccgg 300 cttcgggcac acggcggggc gcgtcccggg cacgttccag ggcgcgcagg gcatgaagcc 360 cgcggcgcgg gagacgcgga cacccccgcg ctcgcccggg ctccgctggg cgctgctgcc 420 gctgctgctg ttgctacgcc agggccaggt cctgtgcgca ggtgcggcac cgaatcctat 480 atttgacatt gaagctgtcg tcagcccaac tagtgtgtta ttaacatgga agcacaatga 540 ctcaggcgct tcagaatgta gaatagagaa taagatggag agcaatctga cgtttcctgt 600 taaaaaccag acatcatgta acattacagg cttaagccca ggcacttcgt atacattctc 660 catcatctct gtaacaacca atgagacctt gaacaaaact atcacaacag agccctggcc 720 agtgtctgat ctccatgtca cctctgtggg tgtgacacag gctcgtctca cctggagcaa 780 tgcaaatggc actgcctcct accggatgct gattgaagag ttgaccacac attcctcagt 840 caatatttca ggtctgaagc cggggaccaa taatacgttc gctttcccag aatcaaatga 900 gacacaggct gactttgcag ttgcagagga ggtcccggat gccaatggta ccaagagaat 960 cccagtgacc aacctatccc aactacacaa gaattctctt gtctctgtgg acccaccctc 1020 tggccaggat ccctccctca cagagatctt gcttactgac ctaaagcctg atactcagta 1080 caatgccacc atctattctc aagcagcaaa tggcactgaa ggacagccca ggaacaaagt 1140 gtttaaaaca aattccaccc aggtttctga cgtccgagct atgaacatca gtgcctcaag 1200 catgaccctg acctggaaaa gcaattacga tgggtcccgt acttcaattg tctacaaaat 1260 acacgtggct ggggggaccc actccgtcaa ccaaactgtc aataagactg aggccatcat 1320 cctcggactc agctccagca ccttgtacaa catcacagtt catcctttcc tgggtcagac 1380 ggagggcaca ccaggcttcc tccaagtgta cacttccccc gatcaggtct ctgacttccg 1440 agtgacaaat gtcagcacaa gggcaattgg tttggcttgg aggagcaatg actccaagtc 1500 cttcgagatt ttcatcaagc aggacggagg tgagaagcat cgaaatgctt cgacgggaaa 1560 ccagagctat atggttgaag atttaaagcc tggaaccagt taccattttg agataattcc 1620 acgaggacca gacgggacag aagggctgtc cagtacagtg aatgggagca ctgaccccag 1680 tgctgtgact gacatccggg tggtcaacat tagcaccact gaaatgcagt tggagtggca 1740 gaatacggac gatgcctctg gatacactta ccatttagtt ctagagtcta aaagtggctc 1800 catcatcagg accaacagtt ctcagaagtg gatcacagta gggagcctca ccccaggcac 1860 cttatacaat gtcacaatct ttccagaagt ggaccagatc cagggaatct ccaactccat 1920 tacccagtac acacggccca gcagtgtgtc ccacattgaa gtaaacacca ccaccaccac 1980 ggcagccatc cgatggaaga acgaggacgc agcctctgct tcctatgcct actccgtcct 2040 tatcttgaag actggagatg gcagcaatgt aaccagcaac ttcacaaaag acccttctat 2100 tctaatccct gagttaatcc ctggtgtctc ttacacagtg aagatcctta cacaagttgg 2160 ggatggtaca acatcactgg tacctggttg gaatctgttc tgtacggaac ctgaaccagt 2220 gacctccttc cactgtgaag tggtccctaa ggagccagca ttggttctca agtgggcctg 2280 cccctttggc atgtacacag gcttcgagct gggggtcagg agtgattcct gggacaatat 2340 gacacgccta gagaactgca cttcggatga tgacacagag tgcaggacgg aagtcgccta 2400 tttgaatttt tctacctcgt acaacatcag catcgccacc ttgtcatgtg ggaagatggc 2460 gcttcccgcc cagaacatct gcaccactgg catcacagac ccacctactc cggatggatc 2520 ccctaatatt acatcggtca gtcacaattc agtaaaggtt aagttcagcg ggtttgaagc 2580 cagccacgga cctatcaaag cctatgctgt catcctcacc accggggaag ctgcccaacc 2640 ttctgcagat gttttgaagt acacgtatga ggatttcaaa aggggagcct cggatactta 2700 tgtcacatac ctcataagaa tagaagagaa gggacagtct cagggcttgt ctgaagtctt 2760 gaactatgaa attgatgtgg ggaaccaatc cactaccctc ggctactaca acgggaggct 2820 ggagcctctg ggctcctacc gggcttgtgt tgctggcttt accaatatta cctacaacct 2880 tcagaatgac ggcctcatca atggggatga gagctatgtg tctttcagtc catattcaga 2940 ggccgtgttc ttgccccagg acccaggtgt catctgcgga gcagtgtttg gatgtatctt 3000 tggtgccctg gccatcacag ctgtgggagg cttcatcttc tggagaaaga aaaggacaga 3060 tgccaagaat aatgaagtgt ccttttctca aattaaacct aaaaaatcca agttaatccg 3120 agtggagaat tttgaggcct actttaagaa gcagcaagct gactctaact gtgggtttgc 3180 agaggaatat gaggacctga agctgattgg gataagttta cctaaataca cagctgagat 3240 agccgagaac agagggaaga accgctacaa caatgttctg ccctatgata tttctcgagt 3300 caaactttca gtccagaccc attcgacaga tgactacatc aatgccaact atatgcctgg 3360 ctaccattcc aagaaagatt tcattgccac acaaggacct ttacccaaca ctttgaaaga 3420 tttctggcgt atggtttggg agaaaaacgt atatgccatt gttatgttga ccaaatgcgt 3480 ggagcaggga aggaccaaat gtgaggagta ctggccttcc aagcaggctc aggactacgg 3540 ggacataact gtggcgatga catcagaagt cgttcttcca gaatggacca tcagagattt 3600 tgtggtgaaa aatatgcaga atagcgagag ccatcctctg cggcagttcc atttcacctc 3660 ctggcctgac cacggtgttc ctgacaccac tgacctgctc atcaactttc ggtacctggt 3720 ccgggattac atgaagcaga taccccccga gtcaccaatt ctggtgcatt gcagtgctgg 3780 ggttggaagg acgggcactt tcatcgccat cgatcgcctg atctatcaga tagagaatga 3840 gaacaccgtg gacgtgtatg ggattgtcta tgaccttcgg atgcacaggc ctctgatggt 3900 gcagacagag gaccagtatg ttttcctcaa tcagtgtgtt ttggatatta tcagagccca 3960 gaaagactca aaagttgatc tcatctatca gaacacaacg gcaatgacaa tctatgaaaa 4020 cctcgagcca gtgagcatgt ttggaaagac taatggttac atcgcctagt tccaaagcaa 4080 acccttttct gaagctaacc ggaccgtcac acccacagtg aaggagagcg ccctgacggg 4140 acatgtttta tatgctcctt tctcagttct ttgttctgtt ctgttagaac tacttggagg 4200 gcatggggct gtgcgtgcaa aagcatggca gatagccagt ggggtgtcag gggctgtgga 4260 cgggtggtgt ggaaatcagc tgccttcctg atcactaatg ggatgggtca ctttttgttt 4320 ttttccttga gaattgtgga aaaccaggaa aagtgagcta tgttttgttt tccaaactgg 4380 tttgttctcc tcttttctcc ccttgtctcc cccctctccc tccccc 4426 <210> SEQ ID NO 47 <211> LENGTH: 1238 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 47 Met Lys Pro Ala Ala Arg Glu Thr Arg Thr Pro Pro Arg Ser Pro Gly 1 5 10 15 Leu Arg Trp Ala Leu Leu Pro Leu Leu Leu Leu Leu Arg Gln Gly Gln 20 25 30 Val Leu Cys Ala Gly Ala Ala Pro Asn Pro Ile Phe Asp Ile Glu Ala 35 40 45 Val Val Ser Pro Thr Ser Val Leu Leu Thr Trp Lys His Asn Asp Ser 50 55 60 Gly Ala Ser Glu Cys Arg Ile Glu Asn Lys Met Glu Ser Asn Leu Thr 65 70 75 80 Phe Pro Val Lys Asn Gln Thr Ser Cys Asn Ile Thr Gly Leu Ser Pro 85 90 95 Gly Thr Ser Tyr Thr Phe Ser Ile Ile Ser Val Thr Thr Asn Glu Thr 100 105 110 Leu Asn Lys Thr Ile Thr Thr Glu Pro Trp Pro Val Ser Asp Leu His 115 120 125 Val Thr Ser Val Gly Val Thr Gln Ala Arg Leu Thr Trp Ser Asn Ala 130 135 140 Asn Gly Thr Ala Ser Tyr Arg Met Leu Ile Glu Glu Leu Thr Thr His 145 150 155 160 Ser Ser Val Asn Ile Ser Gly Leu Lys Pro Gly Thr Asn Asn Thr Phe 165 170 175 Ala Phe Pro Glu Ser Asn Glu Thr Gln Ala Asp Phe Ala Val Ala Glu 180 185 190 Glu Val Pro Asp Ala Asn Gly Thr Lys Arg Ile Pro Val Thr Asn Leu 195 200 205 Ser Gln Leu His Lys Asn Ser Leu Val Ser Val Asp Pro Pro Ser Gly 210 215 220 Gln Asp Pro Ser Leu Thr Glu Ile Leu Leu Thr Asp Leu Lys Pro Asp 225 230 235 240 Thr Gln Tyr Asn Ala Thr Ile Tyr Ser Gln Ala Ala Asn Gly Thr Glu 245 250 255 Gly Gln Pro Arg Asn Lys Val Phe Lys Thr Asn Ser Thr Gln Val Ser 260 265 270 Asp Val Arg Ala Met Asn Ile Ser Ala Ser Ser Met Thr Leu Thr Trp 275 280 285 Lys Ser Asn Tyr Asp Gly Ser Arg Thr Ser Ile Val Tyr Lys Ile His 290 295 300 Val Ala Gly Gly Thr His Ser Val Asn Gln Thr Val Asn Lys Thr Glu 305 310 315 320 Ala Ile Ile Leu Gly Leu Ser Ser Ser Thr Leu Tyr Asn Ile Thr Val 325 330 335 His Pro Phe Leu Gly Gln Thr Glu Gly Thr Pro Gly Phe Leu Gln Val 340 345 350 Tyr Thr Ser Pro Asp Gln Val Ser Asp Phe Arg Val Thr Asn Val Ser 355 360 365 Thr Arg Ala Ile Gly Leu Ala Trp Arg Ser Asn Asp Ser Lys Ser Phe 370 375 380 Glu Ile Phe Ile Lys Gln Asp Gly Gly Glu Lys His Arg Asn Ala Ser 385 390 395 400 Thr Gly Asn Gln Ser Tyr Met Val Glu Asp Leu Lys Pro Gly Thr Ser 405 410 415 Tyr His Phe Glu Ile Ile Pro Arg Gly Pro Asp Gly Thr Glu Gly Leu 420 425 430 Ser Ser Thr Val Asn Gly Ser Thr Asp Pro Ser Ala Val Thr Asp Ile 435 440 445 Arg Val Val Asn Ile Ser Thr Thr Glu Met Gln Leu Glu Trp Gln Asn 450 455 460 Thr Asp Asp Ala Ser Gly Tyr Thr Tyr His Leu Val Leu Glu Ser Lys 465 470 475 480 Ser Gly Ser Ile Ile Arg Thr Asn Ser Ser Gln Lys Trp Ile Thr Val 485 490 495 Gly Ser Leu Thr Pro Gly Thr Leu Tyr Asn Val Thr Ile Phe Pro Glu 500 505 510 Val Asp Gln Ile Gln Gly Ile Ser Asn Ser Ile Thr Gln Tyr Thr Arg 515 520 525 Pro Ser Ser Val Ser His Ile Glu Val Asn Thr Thr Thr Thr Thr Ala 530 535 540 Ala Ile Arg Trp Lys Asn Glu Asp Ala Ala Ser Ala Ser Tyr Ala Tyr 545 550 555 560 Ser Val Leu Ile Leu Lys Thr Gly Asp Gly Ser Asn Val Thr Ser Asn 565 570 575 Phe Thr Lys Asp Pro Ser Ile Leu Ile Pro Glu Leu Ile Pro Gly Val 580 585 590 Ser Tyr Thr Val Lys Ile Leu Thr Gln Val Gly Asp Gly Thr Thr Ser 595 600 605 Leu Val Pro Gly Trp Asn Leu Phe Cys Thr Glu Pro Glu Pro Val Thr 610 615 620 Ser Phe His Cys Glu Val Val Pro Lys Glu Pro Ala Leu Val Leu Lys 625 630 635 640 Trp Ala Cys Pro Phe Gly Met Tyr Thr Gly Phe Glu Leu Gly Val Arg 645 650 655 Ser Asp Ser Trp Asp Asn Met Thr Arg Leu Glu Asn Cys Thr Ser Asp 660 665 670 Asp Asp Thr Glu Cys Arg Thr Glu Val Ala Tyr Leu Asn Phe Ser Thr 675 680 685 Ser Tyr Asn Ile Ser Ile Ala Thr Leu Ser Cys Gly Lys Met Ala Leu 690 695 700 Pro Ala Gln Asn Ile Cys Thr Thr Gly Ile Thr Asp Pro Pro Thr Pro 705 710 715 720 Asp Gly Ser Pro Asn Ile Thr Ser Val Ser His Asn Ser Val Lys Val 725 730 735 Lys Phe Ser Gly Phe Glu Ala Ser His Gly Pro Ile Lys Ala Tyr Ala 740 745 750 Val Ile Leu Thr Thr Gly Glu Ala Ala Gln Pro Ser Ala Asp Val Leu 755 760 765 Lys Tyr Thr Tyr Glu Asp Phe Lys Arg Gly Ala Ser Asp Thr Tyr Val 770 775 780 Thr Tyr Leu Ile Arg Ile Glu Glu Lys Gly Gln Ser Gln Gly Leu Ser 785 790 795 800 Glu Val Leu Asn Tyr Glu Ile Asp Val Gly Asn Gln Ser Thr Thr Leu 805 810 815 Gly Tyr Tyr Asn Gly Arg Leu Glu Pro Leu Gly Ser Tyr Arg Ala Cys 820 825 830 Val Ala Gly Phe Thr Asn Ile Thr Tyr Asn Leu Gln Asn Asp Gly Leu 835 840 845 Ile Asn Gly Asp Glu Ser Tyr Val Ser Phe Ser Pro Tyr Ser Glu Ala 850 855 860 Val Phe Leu Pro Gln Asp Pro Gly Val Ile Cys Gly Ala Val Phe Gly 865 870 875 880 Cys Ile Phe Gly Ala Leu Ala Ile Thr Ala Val Gly Gly Phe Ile Phe 885 890 895 Trp Arg Lys Lys Arg Thr Asp Ala Lys Asn Asn Glu Val Ser Phe Ser 900 905 910 Gln Ile Lys Pro Lys Lys Ser Lys Leu Ile Arg Val Glu Asn Phe Glu 915 920 925 Ala Tyr Phe Lys Lys Gln Gln Ala Asp Ser Asn Cys Gly Phe Ala Glu 930 935 940 Glu Tyr Glu Asp Leu Lys Leu Ile Gly Ile Ser Leu Pro Lys Tyr Thr 945 950 955 960 Ala Glu Ile Ala Glu Asn Arg Gly Lys Asn Arg Tyr Asn Asn Val Leu 965 970 975 Pro Tyr Asp Ile Ser Arg Val Lys Leu Ser Val Gln Thr His Ser Thr 980 985 990 Asp Asp Tyr Ile Asn Ala Asn Tyr Met Pro Gly Tyr His Ser Lys Lys 995 1000 1005 Asp Phe Ile Ala Thr Gln Gly Pro Leu Pro Asn Thr Leu Lys Asp Phe 1010 1015 1020 Trp Arg Met Val Trp Glu Lys Asn Val Tyr Ala Ile Val Met Leu Thr 1025 1030 1035 1040 Lys Cys Val Glu Gln Gly Arg Thr Lys Cys Glu Glu Tyr Trp Pro Ser 1045 1050 1055 Lys Gln Ala Gln Asp Tyr Gly Asp Ile Thr Val Ala Met Thr Ser Glu 1060 1065 1070 Val Val Leu Pro Glu Trp Thr Ile Arg Asp Phe Val Val Lys Asn Met 1075 1080 1085 Gln Asn Ser Glu Ser His Pro Leu Arg Gln Phe His Phe Thr Ser Trp 1090 1095 1100 Pro Asp His Gly Val Pro Asp Thr Thr Asp Leu Leu Ile Asn Phe Arg 1105 1110 1115 1120 Tyr Leu Val Arg Asp Tyr Met Lys Gln Ile Pro Pro Glu Ser Pro Ile 1125 1130 1135 Leu Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr Phe Ile Ala 1140 1145 1150 Ile Asp Arg Leu Ile Tyr Gln Ile Glu Asn Glu Asn Thr Val Asp Val 1155 1160 1165 Tyr Gly Ile Val Tyr Asp Leu Arg Met His Arg Pro Leu Met Val Gln 1170 1175 1180 Thr Glu Asp Gln Tyr Val Phe Leu Asn Gln Cys Val Leu Asp Ile Ile 1185 1190 1195 1200 Arg Ala Gln Lys Asp Ser Lys Val Asp Leu Ile Tyr Gln Asn Thr Thr 1205 1210 1215 Ala Met Thr Ile Tyr Glu Asn Leu Glu Pro Val Ser Met Phe Gly Lys 1220 1225 1230 Thr Asn Gly Tyr Ile Ala 1235 <210> SEQ ID NO 48 <211> LENGTH: 6314 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus` <400> SEQUENCE: 48 ggaaacccgg gacggacgga gcggggacta ggcggaccga ctggcggaga aggaggcgga 60 ggcgtcgact ggagacggag accagggcgc ccggcttcgg gcacacggcg gggcgcgtcc 120 cgggcacgtt ccagggcgcg cagggcatga agcccgcggc gcgggagacg cggacacccc 180 cgcgctcgcc cgggctccgc tgggcgctgc tgccgctgct gctgttgcta cgccagggcc 240 aggttgtgtg cacaggtgcg gcgcccagtc ctgtatttga cgttgaagct gtcaccagcc 300 ctaccagtgt ggtattaacg tggaaacaca atgattcagc cacttcagaa tataagataa 360 atgagggaaa cacgctgcgg tatactgtta aaaaccagac atcatttaac atcacaggct 420 taagcccagc tacttcctac aaattctcca tcaccttggg aacagtcaat gagacctcag 480 gaaagcccac atacaaaaat atcacaacag agccctggcc agtgtcggat ctccaagtcg 540 cctacatcgg tgtgacacag gctcttctcg cctggagcaa tgcaaacggc accgcttctt 600 accggatgca gattgtagag ctgaccacaa attcatcagg tggtatttca gatctgaagc 660 cggggaccca taagagcttg gctgtccaag gatcgaatga gacccagcat gacttatggg 720 tcacagaagg cgtctcggac ccaccctctg cccgggatcc ctccctcaca gaggtcttgc 780 tcactgagct aaagcctgat actcagtaca aagtcaccat ttattctcaa gcagcagatg 840 gcacagaagg acagcctggg aacaaagtgt ttaaaacaaa tcccatccaa gtttctgaca 900 tccgagctgt gaacatcagt gactcgaaca tgaccctgac ctggaaaagc aacaataatg 960 agtcccatgc ttcatttacc tacaaaatat acgtggctgg gggttccgac tccatcaacg 1020 aaactgtcaa tgagactcag gccgtcatcc gtggactcag ctccagtacc ttgtacaaca 1080 tcacagtgct tcctttcctg ggtcagaccg cgggtatacc aggcttcctc caagtgtaca 1140 cttccccccg tcctgtttct gacttccgag tgacaaatgt cagcctgagg gaaatcggtt 1200 tggcttggag aagcaatgac tcggagtcat tcgagatttt catcacgcag gagggaagtg 1260 agaaacgttg gaatgcttcg acgggagacc tgagctatat cgttgtaaat ttaaagcctg 1320 ggaccagtta ccaatttgaa atattcccac gaggaccaaa tgggactgaa gggccatccc 1380 agacagttgt tggtagaact gactgcagtg ctgtgactga catccgcgtg gtcagcgtta 1440 gcaccactga aatacagctg gagtggcaga atacagacag tgcttctgga tacacttacc 1500 atttagttct agagtctgag aatggctcca tcaagaccaa cagttctcag aaatggatca 1560 cagtgggggg ccttacccca ggcaccttat acaatgttac aatctttcca gaagtggacc 1620 agatggaggg caactccagc tctattaccc agtacacaag gcccagcaat gtgtcctaca 1680 ttgaagtaaa caccaacacc accgtgggag ccatccagtg gaagaacctg gacgcagcct 1740 ctgcttccta ctcctactcc gttcttatct tgaaggctgg agatggcagc aatgtaacca 1800 gcagggtcag agacatccct tctgtcacca tccctgggct aatccccggc gtctcttccg 1860 aagtgaagat ctttacaaag attaggaata cagaggttgg gaatgaggta cctggtcaga 1920 agctgttctg tatggaacct gcacaagtgg attccttaca ctgtgaagtg gtcccgaagg 1980 agccagcgct ggttctgaag tgggcctgcc cccctggcat gaactcaggc tttgaactgg 2040 gggtcaggag tgatgcttgg gacaatatga cacacttgga gaactgcact ttggacaatg 2100 acacagagtg caggacagaa gtcacctatt tgaatttttc tacctcgtac aacatcagca 2160 ttgccacctt gtcatgtgga aagatggcat tgcccaccca gagcacctgc accactggca 2220 tcacagaccc acctcctcca gatggatccc ctaatattac atcggtcagt cacaattcag 2280 taaaggtgaa gttcagtggt tttgaagcca gccatggacc tatcaaagcc tatgctgtcc 2340 ttctcaccac aggggaagct ggccaaccct ccacagatgt tttgaagtac acatatgaag 2400 atttcaaaaa gggagcctcc gatacttatg tgacatacct cataaggata gaagagaagg 2460 gacagtctca gggcttgtct gaagcattga actatgagat tgatgtgggg aaccaatcca 2520 ctaccctcgg ctactacaac gggaggctag agcctctggg ctcctaccgg gcttgcgttg 2580 ctggctttac caatattacc tacaaccttc agaacgatgg ccttattaat ggggatgaga 2640 gctatgtatc tttcagtccg tattcagagg ccgtgtcctt gcctcaagat ccaggtgtca 2700 tctgcggagc ggtgttcgga tgtatctttg gtgccctggc cattgtggct gtgggaggct 2760 tcatcttctg gagaaagaaa aggaaagatg ccaagaataa tgaagtgtcc ttttctcaaa 2820 ttaaacctaa aaaatccaag ttaatccgag tggagaattt tgaggcctac tttaagaaac 2880 agcaagccga ctccaactgt gggtttgcag aggaatatga ggatctgaag ctgattggaa 2940 taagtttacc taaatatgca gcggaaatag ctgaaaacag ggggaagaac cgctacaaca 3000 acgtcctgcc ctatgatatt tctcgagtca aactttcagt ccagacccat tcgacagacg 3060 actacatcaa tgccaactat atgcctggct accattccaa gaaagatttc attgccacac 3120 aaggaccttt acccaacact ttgaaagatt tttggcgtat ggtttgggag aaaaacgtat 3180 atgccattgt tatgctgacc aaatgtgtgg agcagggaag gaccaaatgt gaagagtact 3240 ggccttccaa gcaggctcag gactacgggg acataactgt ggcaatgaca tcagaagttg 3300 ttcttccgga atggaccatc agagattttg tggtgaaaaa tatgcagagt agtgagagtc 3360 atcctctgcg gcagttccat ttcacctcct ggcctgacca tggtgttcct gacaccaccg 3420 acctgctcat caactttcgg tacctggtcc gggattacat gaagcagatc ccccctgagt 3480 caccaatcct ggtgcattgc agtgctgggg ttggaaggac gggcactttc attgctattg 3540 atcgcctgat ctatcagata gagaacgaga acaccgtgga tgtgtatggc attgtctacg 3600 atcttcggat gcacaggcct ctgatggtac agacagagga ccagtatgtt ttcctcaatc 3660 agtgtgtgtt ggatattatc agagcccaga aagactcaaa agttgacctc atctatcaga 3720 acacaaccgc aatgacaatc tatgaaaacc tcgagcgagt gagcatgttt ggaaaggcta 3780 atggttacat cgcctagtgc caaagcaaac ccttctgaag ctaaccagac cgtcacaccc 3840 acagtgaagg agaacgccct gacggggaca tgttttatgt gtctcatttc tcaattcttt 3900 gttctgttct gttagaacta cttggagggc atggggctgt gcatgtaaaa catggcagat 3960 aggcagttgg ggctctcagg ggctgtgggc aggtggtgtg taaatcagct gcattcctga 4020 ttaccaatgg gatgggttca ctttctgttt ttctttcctt gagaattgtg gaaaaccagg 4080 aaaagtgagc tatgtttttg ttttccaagc aggtttgttc tcctctcttt ctattcctcc 4140 cccttctctc tctccctccc ctgcctctct ctgttttttt tttttaagac ttttatatga 4200 ttcacatgct aaagccagga ttatgttggg ttggatatat tttaagtatc agaggtctat 4260 ttttacctac tgtatctcgg aatctagccg atggaaaagc atggctgtgg gtgtttctca 4320 tgcagggagg ggcacccggt gcctcttctg cgtgggtttc tatttgaaca tgtgcctttt 4380 ctgaattatg cttccacggg caaaactcag tagatatctc tatttttata ttgaatctca 4440 gaattggaat atacagaata tttaaacagt agcttagtat cagaggttcg cctcctcagt 4500 aacattcctg tcccatccca ttagaggagg ctttctctgc ggcccgccct tgacacacat 4560 ttgtgctcca tgttcctttt ccttcctttc tttttttttt tttctcccct cccagttttc 4620 gccaaagaac ttctgttggt gagattttca tcccattggt tgggtgagaa tagaagttta 4680 aaatatcacc atgagactct ctgtgggtgg gagtggggag gaacagagga atcaacatac 4740 catggtgtgt gcaccccttt tcatcccgcc tcctatgttc tctcatttct gtctttggta 4800 agaaggattt ttttaaaggt gcaatatgtg acgtgggggt tcacgatgct ctgggttctt 4860 agtaatgttt tactcaggtt gtcatttatg tgtgtatgtg tgtgtgtgtg tgtgtgtgtg 4920 tgtgtgtgtg tgtatgtatg tatgtgtgtt ttatagcgtg gtgatctgtg aacatttcag 4980 tgtgaactca gattaacccc tttcccccca aagtccactg gctttagtct ctctgcagtg 5040 acacacatca gtatctactg tatatataaa tactaaactc ttacacacca gtcattccta 5100 tgaattgagg tgtacaaagt ttgatttgta tcaaagatgt aattattatt tttaaaacct 5160 ctttcactac actgctgctg taattacttt gaatttttaa agaaaaatgt agattttttt 5220 gttttgtttt tggcttcagg tgtgtattca ccaagagttt cagaatttat gtggttttat 5280 tttattggta cataatctgc aaacttctca aggcattaac atgacaagat ttgtatctct 5340 tatttttatc ttgtggctca ggttatattt gaagaagttt caagtttatt ttctagtagg 5400 cagtgaagta tacataaggt caatgaagga atcaccaggt ccctggagtc ctgtggctgt 5460 tttccacagt tacacatcct gctgtatgtt tgggaccatg ggtattgtgt tgaagatgag 5520 ggcaggggtc ttctccgagg acctggccac tgtgagccct ggggtaacct gtcctctgat 5580 gttctgcact ctgttcctcg aatcaccggc actttgatgc ctgactggac ctgatcatga 5640 gtgtttgtag ggttagagag cctgaaccat gatgtactga aagccctcgc tgtggttcag 5700 cactgtagtg tgcgattctt gctgtgaccc agcgctgctg tagcactgtt gctgccgtgg 5760 ctcggcgctg gggcacaacc cctttccctt tgcggtactg aaaggattga aagaagaggt 5820 catggcgctg tcatgctctg ggggagaatt ttacttctca catggaaact gcactttttg 5880 ctaaatcctt tgcattttga tgttcactta gtgtccagcc ctttaggatg ggctggccag 5940 ggtaggttgg ccccctggac tcaacttcac tggggaactt gacgctgcag ttgtgaatca 6000 gggaagccat gctgtctcca ggtatggggt gaagctgaac atgggctcat tatttccaaa 6060 tgccctgtct ggtctgctca ctaggatgtg ctgactttgg gcactataca gaggggcctg 6120 ttctggcagt agttctgtgc accgcctata cacctcagtc tgtcaggaac ggttgtagtg 6180 ggtggtaagg ggtccaatcc cacgcagcgc ctatgccctg cctctgctgc catggaaagt 6240 gcgaggaaag gacccgcccc taaaacagcc ctgtagaaga ttagagtccc tcaaaaaaaa 6300 aaaaaaaact cgag 6314 <210> SEQ ID NO 49 <211> LENGTH: 1216 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 49 Met Lys Pro Ala Ala Arg Glu Thr Arg Thr Pro Pro Arg Ser Pro Gly 1 5 10 15 Leu Arg Trp Ala Leu Leu Pro Leu Leu Leu Leu Leu Arg Gln Gly Gln 20 25 30 Val Val Cys Thr Gly Ala Ala Pro Ser Pro Val Phe Asp Val Glu Ala 35 40 45 Val Thr Ser Pro Thr Ser Val Val Leu Thr Trp Lys His Asn Asp Ser 50 55 60 Ala Thr Ser Glu Tyr Lys Ile Asn Glu Gly Asn Thr Leu Arg Tyr Thr 65 70 75 80 Val Lys Asn Gln Thr Ser Phe Asn Ile Thr Gly Leu Ser Pro Ala Thr 85 90 95 Ser Tyr Lys Phe Ser Ile Thr Leu Gly Thr Val Asn Glu Thr Ser Gly 100 105 110 Lys Pro Thr Tyr Lys Asn Ile Thr Thr Glu Pro Trp Pro Val Ser Asp 115 120 125 Leu Gln Val Ala Tyr Ile Gly Val Thr Gln Ala Leu Leu Ala Trp Ser 130 135 140 Asn Ala Asn Gly Thr Ala Ser Tyr Arg Met Gln Ile Val Glu Leu Thr 145 150 155 160 Thr Asn Ser Ser Gly Gly Ile Ser Asp Leu Lys Pro Gly Thr His Lys 165 170 175 Ser Leu Ala Val Gln Gly Ser Asn Glu Thr Gln His Asp Leu Trp Val 180 185 190 Thr Glu Gly Val Ser Asp Pro Pro Ser Ala Arg Asp Pro Ser Leu Thr 195 200 205 Glu Val Leu Leu Thr Glu Leu Lys Pro Asp Thr Gln Tyr Lys Val Thr 210 215 220 Ile Tyr Ser Gln Ala Ala Asp Gly Thr Glu Gly Gln Pro Gly Asn Lys 225 230 235 240 Val Phe Lys Thr Asn Pro Ile Gln Val Ser Asp Ile Arg Ala Val Asn 245 250 255 Ile Ser Asp Ser Asn Met Thr Leu Thr Trp Lys Ser Asn Asn Asn Glu 260 265 270 Ser His Ala Ser Phe Thr Tyr Lys Ile Tyr Val Ala Gly Gly Ser Asp 275 280 285 Ser Ile Asn Glu Thr Val Asn Glu Thr Gln Ala Val Ile Arg Gly Leu 290 295 300 Ser Ser Ser Thr Leu Tyr Asn Ile Thr Val Leu Pro Phe Leu Gly Gln 305 310 315 320 Thr Ala Gly Ile Pro Gly Phe Leu Gln Val Tyr Thr Ser Pro Arg Pro 325 330 335 Val Ser Asp Phe Arg Val Thr Asn Val Ser Leu Arg Glu Ile Gly Leu 340 345 350 Ala Trp Arg Ser Asn Asp Ser Glu Ser Phe Glu Ile Phe Ile Thr Gln 355 360 365 Glu Gly Ser Glu Lys Arg Trp Asn Ala Ser Thr Gly Asp Leu Ser Tyr 370 375 380 Ile Val Val Asn Leu Lys Pro Gly Thr Ser Tyr Gln Phe Glu Ile Phe 385 390 395 400 Pro Arg Gly Pro Asn Gly Thr Glu Gly Pro Ser Gln Thr Val Val Gly 405 410 415 Arg Thr Asp Cys Ser Ala Val Thr Asp Ile Arg Val Val Ser Val Ser 420 425 430 Thr Thr Glu Ile Gln Leu Glu Trp Gln Asn Thr Asp Ser Ala Ser Gly 435 440 445 Tyr Thr Tyr His Leu Val Leu Glu Ser Glu Asn Gly Ser Ile Lys Thr 450 455 460 Asn Ser Ser Gln Lys Trp Ile Thr Val Gly Gly Leu Thr Pro Gly Thr 465 470 475 480 Leu Tyr Asn Val Thr Ile Phe Pro Glu Val Asp Gln Met Glu Gly Asn 485 490 495 Ser Ser Ser Ile Thr Gln Tyr Thr Arg Pro Ser Asn Val Ser Tyr Ile 500 505 510 Glu Val Asn Thr Asn Thr Thr Val Gly Ala Ile Gln Trp Lys Asn Leu 515 520 525 Asp Ala Ala Ser Ala Ser Tyr Ser Tyr Ser Val Leu Ile Leu Lys Ala 530 535 540 Gly Asp Gly Ser Asn Val Thr Ser Arg Val Arg Asp Ile Pro Ser Val 545 550 555 560 Thr Ile Pro Gly Leu Ile Pro Gly Val Ser Ser Glu Val Lys Ile Phe 565 570 575 Thr Lys Ile Arg Asn Thr Glu Val Gly Asn Glu Val Pro Gly Gln Lys 580 585 590 Leu Phe Cys Met Glu Pro Ala Gln Val Asp Ser Leu His Cys Glu Val 595 600 605 Val Pro Lys Glu Pro Ala Leu Val Leu Lys Trp Ala Cys Pro Pro Gly 610 615 620 Met Asn Ser Gly Phe Glu Leu Gly Val Arg Ser Asp Ala Trp Asp Asn 625 630 635 640 Met Thr His Leu Glu Asn Cys Thr Leu Asp Asn Asp Thr Glu Cys Arg 645 650 655 Thr Glu Val Thr Tyr Leu Asn Phe Ser Thr Ser Tyr Asn Ile Ser Ile 660 665 670 Ala Thr Leu Ser Cys Gly Lys Met Ala Leu Pro Thr Gln Ser Thr Cys 675 680 685 Thr Thr Gly Ile Thr Asp Pro Pro Pro Pro Asp Gly Ser Pro Asn Ile 690 695 700 Thr Ser Val Ser His Asn Ser Val Lys Val Lys Phe Ser Gly Phe Glu 705 710 715 720 Ala Ser His Gly Pro Ile Lys Ala Tyr Ala Val Leu Leu Thr Thr Gly 725 730 735 Glu Ala Gly Gln Pro Ser Thr Asp Val Leu Lys Tyr Thr Tyr Glu Asp 740 745 750 Phe Lys Lys Gly Ala Ser Asp Thr Tyr Val Thr Tyr Leu Ile Arg Ile 755 760 765 Glu Glu Lys Gly Gln Ser Gln Gly Leu Ser Glu Ala Leu Asn Tyr Glu 770 775 780 Ile Asp Val Gly Asn Gln Ser Thr Thr Leu Gly Tyr Tyr Asn Gly Arg 785 790 795 800 Leu Glu Pro Leu Gly Ser Tyr Arg Ala Cys Val Ala Gly Phe Thr Asn 805 810 815 Ile Thr Tyr Asn Leu Gln Asn Asp Gly Leu Ile Asn Gly Asp Glu Ser 820 825 830 Tyr Val Ser Phe Ser Pro Tyr Ser Glu Ala Val Ser Leu Pro Gln Asp 835 840 845 Pro Gly Val Ile Cys Gly Ala Val Phe Gly Cys Ile Phe Gly Ala Leu 850 855 860 Ala Ile Val Ala Val Gly Gly Phe Ile Phe Trp Arg Lys Lys Arg Lys 865 870 875 880 Asp Ala Lys Asn Asn Glu Val Ser Phe Ser Gln Ile Lys Pro Lys Lys 885 890 895 Ser Lys Leu Ile Arg Val Glu Asn Phe Glu Ala Tyr Phe Lys Lys Gln 900 905 910 Gln Ala Asp Ser Asn Cys Gly Phe Ala Glu Glu Tyr Glu Asp Leu Lys 915 920 925 Leu Ile Gly Ile Ser Leu Pro Lys Tyr Ala Ala Glu Ile Ala Glu Asn 930 935 940 Arg Gly Lys Asn Arg Tyr Asn Asn Val Leu Pro Tyr Asp Ile Ser Arg 945 950 955 960 Val Lys Leu Ser Val Gln Thr His Ser Thr Asp Asp Tyr Ile Asn Ala 965 970 975 Asn Tyr Met Pro Gly Tyr His Ser Lys Lys Asp Phe Ile Ala Thr Gln 980 985 990 Gly Pro Leu Pro Asn Thr Leu Lys Asp Phe Trp Arg Met Val Trp Glu 995 1000 1005 Lys Asn Val Tyr Ala Ile Val Met Leu Thr Lys Cys Val Glu Gln Gly 1010 1015 1020 Arg Thr Lys Cys Glu Glu Tyr Trp Pro Ser Lys Gln Ala Gln Asp Tyr 1025 1030 1035 1040 Gly Asp Ile Thr Val Ala Met Thr Ser Glu Val Val Leu Pro Glu Trp 1045 1050 1055 Thr Ile Arg Asp Phe Val Val Lys Asn Met Gln Ser Ser Glu Ser His 1060 1065 1070 Pro Leu Arg Gln Phe His Phe Thr Ser Trp Pro Asp His Gly Val Pro 1075 1080 1085 Asp Thr Thr Asp Leu Leu Ile Asn Phe Arg Tyr Leu Val Arg Asp Tyr 1090 1095 1100 Met Lys Gln Ile Pro Pro Glu Ser Pro Ile Leu Val His Cys Ser Ala 1105 1110 1115 1120 Gly Val Gly Arg Thr Gly Thr Phe Ile Ala Ile Asp Arg Leu Ile Tyr 1125 1130 1135 Gln Ile Glu Asn Glu Asn Thr Val Asp Val Tyr Gly Ile Val Tyr Asp 1140 1145 1150 Leu Arg Met His Arg Pro Leu Met Val Gln Thr Glu Asp Gln Tyr Val 1155 1160 1165 Phe Leu Asn Gln Cys Val Leu Asp Ile Ile Arg Ala Gln Lys Asp Ser 1170 1175 1180 Lys Val Asp Leu Ile Tyr Gln Asn Thr Thr Ala Met Thr Ile Tyr Glu 1185 1190 1195 1200 Asn Leu Glu Arg Val Ser Met Phe Gly Lys Ala Asn Gly Tyr Ile Ala 1205 1210 1215 <210> SEQ ID NO 50 <211> LENGTH: 1785 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 50 atggcagcgg agtcagggga actaatcggg gcttgtgagt tcatgaaaga tcggttatat 60 tttgctactt taaggaatag accaaaaagc acagtaaata cccactattt ctccatcgat 120 gaggagctgg tctatgaaaa tttctatgca gattttggac cgctgaactt ggcaatggtg 180 tacagatatt gctgcaaact aaacaagaaa ctaaaatcat acagtttgtc aagaaagaaa 240 atagtgcact acacctgttt tgaccaacgg aaaagagcaa atgcagcatt tttgataggt 300 gcctatgcag taatctattt aaagaagaca ccagaagaag cctacagagc actcctgtct 360 ggctcaaacc ccccctatct tccattcagg gatgcttcct ttggaaattg cacttacaat 420 ctcaccattc tcgactgttt gcagggaatc agaaagggat tacaacatgg attttttgac 480 tttgagacat ttgatgtgga tgaatatgaa cattatgagc gagttgaaaa tggtgacttc 540 aactggattg ttccaggaaa atttttagca tttagtggac cacatcctaa aagcaaaatt 600 gagaatggtt atcctcttca cgcccctgaa gcctactttc cttatttcaa aaagcataat 660 gtgactgcag ttgtgaggct aaacaaaaag atttatgagg caaagcgctt cacagacgct 720 ggcttcgagc actatgacct cttcttcata gatggcagca cacccagtga caacatcgtg 780 cgaaggttcc tgaacatctg tgagaacacc gaaggggcca tcgccgttca ctgcaaagct 840 ggtcttggaa gaacagggac attgatagcc tgttatgtaa tgaaacacta caggtttaca 900 catgctgaaa taattgcttg gattagaata tgccggccag gctctattat aggaccccag 960 cagcacttcc tggaagaaaa acaagcatcg ttgtgggtcc aaggagacat tttccgatcc 1020 aaactgaaaa atcgaccatc cagtgaagga agtattaata aaattctttc tggcctagat 1080 gatatgtcta ttggtggaaa tctttcaaaa acacaaaaca tggaacgatt tggagaggat 1140 aacttagaag atgatgatgt ggaaatgaaa aatggtataa cccagggaga caaactacgt 1200 gccttaaaaa gtcagagaca gccacgtacc tcaccatcct gtgcatttag gtcagatgat 1260 acaaaaggac atccaagagc agtgtcccag cctttcagat taagttcatc cctgcaagga 1320 tctgcagtta ctttgaagac atcaaaaatg gcactgtccc cttcagcaac ggccaagagg 1380 atcaacagaa cttctttgtc ttcgggtgcc actgtaagaa gcttttccat aaactcccgg 1440 ctagccagtt ctctagggaa cttgaatgct gcaacagatg atccagagaa caaaaagacc 1500 tcctcatcct ctaaggcagg cttcacagcc agcccgttta ccaacctctt gaatggcagc 1560 tcccagccaa ctaccagaaa ttaccctgag ctcaacaata atcagtacaa cagaagcagc 1620 aacagcaacg ggggcaacct gaacagcccc ccaggccccc acagcgccaa gacagaggag 1680 cacaccacca tcctccgacc ctcctacacc gggctttctt cttcttcagc gagattcctg 1740 agccgttcta tcccttccct tcagtctgaa tatgttcatt actaa 1785 <210> SEQ ID NO 51 <211> LENGTH: 594 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 51 Met Ala Ala Glu Ser Gly Glu Leu Ile Gly Ala Cys Glu Phe Met Lys 1 5 10 15 Asp Arg Leu Tyr Phe Ala Thr Leu Arg Asn Arg Pro Lys Ser Thr Val 20 25 30 Asn Thr His Tyr Phe Ser Ile Asp Glu Glu Leu Val Tyr Glu Asn Phe 35 40 45 Tyr Ala Asp Phe Gly Pro Leu Asn Leu Ala Met Val Tyr Arg Tyr Cys 50 55 60 Cys Lys Leu Asn Lys Lys Leu Lys Ser Tyr Ser Leu Ser Arg Lys Lys 65 70 75 80 Ile Val His Tyr Thr Cys Phe Asp Gln Arg Lys Arg Ala Asn Ala Ala 85 90 95 Phe Leu Ile Gly Ala Tyr Ala Val Ile Tyr Leu Lys Lys Thr Pro Glu 100 105 110 Glu Ala Tyr Arg Ala Leu Leu Ser Gly Ser Asn Pro Pro Tyr Leu Pro 115 120 125 Phe Arg Asp Ala Ser Phe Gly Asn Cys Thr Tyr Asn Leu Thr Ile Leu 130 135 140 Asp Cys Leu Gln Gly Ile Arg Lys Gly Leu Gln His Gly Phe Phe Asp 145 150 155 160 Phe Glu Thr Phe Asp Val Asp Glu Tyr Glu His Tyr Glu Arg Val Glu 165 170 175 Asn Gly Asp Phe Asn Trp Ile Val Pro Gly Lys Phe Leu Ala Phe Ser 180 185 190 Gly Pro His Pro Lys Ser Lys Ile Glu Asn Gly Tyr Pro Leu His Ala 195 200 205 Pro Glu Ala Tyr Phe Pro Tyr Phe Lys Lys His Asn Val Thr Ala Val 210 215 220 Val Arg Leu Asn Lys Lys Ile Tyr Glu Ala Lys Arg Phe Thr Asp Ala 225 230 235 240 Gly Phe Glu His Tyr Asp Leu Phe Phe Ile Asp Gly Ser Thr Pro Ser 245 250 255 Asp Asn Ile Val Arg Arg Phe Leu Asn Ile Cys Glu Asn Thr Glu Gly 260 265 270 Ala Ile Ala Val His Cys Lys Ala Gly Leu Gly Arg Thr Gly Thr Leu 275 280 285 Ile Ala Cys Tyr Val Met Lys His Tyr Arg Phe Thr His Ala Glu Ile 290 295 300 Ile Ala Trp Ile Arg Ile Cys Arg Pro Gly Ser Ile Ile Gly Pro Gln 305 310 315 320 Gln His Phe Leu Glu Glu Lys Gln Ala Ser Leu Trp Val Gln Gly Asp 325 330 335 Ile Phe Arg Ser Lys Leu Lys Asn Arg Pro Ser Ser Glu Gly Ser Ile 340 345 350 Asn Lys Ile Leu Ser Gly Leu Asp Asp Met Ser Ile Gly Gly Asn Leu 355 360 365 Ser Lys Thr Gln Asn Met Glu Arg Phe Gly Glu Asp Asn Leu Glu Asp 370 375 380 Asp Asp Val Glu Met Lys Asn Gly Ile Thr Gln Gly Asp Lys Leu Arg 385 390 395 400 Ala Leu Lys Ser Gln Arg Gln Pro Arg Thr Ser Pro Ser Cys Ala Phe 405 410 415 Arg Ser Asp Asp Thr Lys Gly His Pro Arg Ala Val Ser Gln Pro Phe 420 425 430 Arg Leu Ser Ser Ser Leu Gln Gly Ser Ala Val Thr Leu Lys Thr Ser 435 440 445 Lys Met Ala Leu Ser Pro Ser Ala Thr Ala Lys Arg Ile Asn Arg Thr 450 455 460 Ser Leu Ser Ser Gly Ala Thr Val Arg Ser Phe Ser Ile Asn Ser Arg 465 470 475 480 Leu Ala Ser Ser Leu Gly Asn Leu Asn Ala Ala Thr Asp Asp Pro Glu 485 490 495 Asn Lys Lys Thr Ser Ser Ser Ser Lys Ala Gly Phe Thr Ala Ser Pro 500 505 510 Phe Thr Asn Leu Leu Asn Gly Ser Ser Gln Pro Thr Thr Arg Asn Tyr 515 520 525 Pro Glu Leu Asn Asn Asn Gln Tyr Asn Arg Ser Ser Asn Ser Asn Gly 530 535 540 Gly Asn Leu Asn Ser Pro Pro Gly Pro His Ser Ala Lys Thr Glu Glu 545 550 555 560 His Thr Thr Ile Leu Arg Pro Ser Tyr Thr Gly Leu Ser Ser Ser Ser 565 570 575 Ala Arg Phe Leu Ser Arg Ser Ile Pro Ser Leu Gln Ser Glu Tyr Val 580 585 590 His Tyr <210> SEQ ID NO 52 <211> LENGTH: 2438 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 cgaagaggat ccggagcagc tgctgccagc ccgcgggcac tgaagtcctc ccggctgccg 60 ctcgagtagc cacgggcgcg atcgggacca gaagtctcct cctccatgat cactttggaa 120 gccgggggaa gactttgccc tgccctgaga gctggtctgc gtttcccagg cgcggcggcg 180 gcggagcagc agctgcagca gccgagtcca aataggagcg gccacagcca ggggcgtgtg 240 cgccccgcgc ggagcgagct cgggttcccc tcggaatgtc cccggggcgc ccggcgcgct 300 gaccccgaag ccgcctccgc cttcggcgcc tgctgcctcc ctcggccagg cttgttgttc 360 gggactgtga gcttcctggc tcctgggcag tggggaagcc cccgggggcg agtgacctca 420 gctggccacg acccagccct cccccgtgcg tatctcgctt aagatggcag cggagtcagg 480 ggaactaatc ggggcttgtg agttcatgaa agatcggtta tattttgcta ctttaaggaa 540 tagaccaaaa agcacagtaa atacccacta tttctccatc gatgaggagc tggtctatga 600 aaatttctat gcagattttg gaccgctgaa cttggcaatg gtgtacagat attgctgcaa 660 actaaacaag aaactaaaat catacagttt gtcaagaaag aaaatagtgc actacacctg 720 ttttgaccaa cggaaaagag caaatgcagc atttttgata ggtgcctatg cagtaatcta 780 tttaaagaag acaccagaag aagcctacag agcactcctg tctggctcaa acccccccta 840 tcttccattc agggatgctt cctttggaaa ttgcacttac aatctcacca ttctcgactg 900 tttgcaggga atcagaaagg gattacaaca tggatttttt gactttgaga catttgatgt 960 ggatgaatat gaacattatg agcgagttga aaatggtgac ttcaactgga ttgttccagg 1020 aaaattttta gcatttagtg gaccacatcc taaaagcaaa attgagaatg gttatcctct 1080 tcacgcccct gaagcctact ttccttattt caaaaagcat aatgtgactg cagttgtgag 1140 gctaaacaaa aagatttatg aggcaaagcg cttcacagac gctggcttcg agcactatga 1200 cctcttcttc atagatggca gcacacccag tgacaacatc gtgcgaaggt tcctgaacat 1260 ctgtgagaac accgaagggg ccatcgccgt tcactgcaaa gctggtcttg gaagaacagg 1320 gacattgata gcctgttatg taatgaaaca ctacaggttt acacatgctg aaataattgc 1380 ttggattaga atatgccggc caggctctat tataggaccc cagcagcact tcctggaaga 1440 aaaacaagca tcgttgtggg tccaaggaga cattttccga tccaaactga aaaatcgacc 1500 atccagtgaa ggaagtatta ataaaattct ttctggccta gatgatatgt ctattggtgg 1560 aaatctttca aaaacacaaa acatggaacg atttggagag gataacttag aagatgatga 1620 tgtggaaatg aaaaatggta taacccaggg agacaaacta cgtgccttaa aaagtcagag 1680 acagccacgt acctcaccat cctgtgcatt taggtcagat gatacaaaag gacatccaag 1740 agcagtgtcc cagcctttca gattaagttc atccctgcaa ggatctgcag ttactttgaa 1800 gacatcaaaa atggcactgt ccccttcagc aacggccaag aggatcaaca gaacttcttt 1860 gtcttcgggt gccactgtaa gaagcttttc cataaactcc cggctagcca gttctctagg 1920 gaacttgaat gctgcaacag atgatccaga gaacaaaaag acctcctcat cctctaaggc 1980 aggcttcaca gccagcccgt ttaccaacct cttgaatggc agctcccagc caactaccag 2040 aaattaccct gagctcaaca ataatcagta caacagaagc agcaacagca acgggggcaa 2100 cctgaacagc cccccaggcc cccacagcgc caagacagag gagcacacca ccatcctccg 2160 accctcctac accgggcttt cttcttcttc agcgagattc ctgagccgtt ctatccctgt 2220 aagtgcgcag acaccacctc ctggtcctca gaaccctgaa tgcaacttct gtgccttgcc 2280 ttcccagccg aggctgccac caaagaaatt taatagtgcc aaggaagcct tctgagcgat 2340 gccttccctc tgtgctgtga aactgtctat gcactacatt ctgctagctc ctcttcaagt 2400 aaacgccaag tcacaaaaaa aaaaaaaaaa aaaaaaaa 2438 <210> SEQ ID NO 53 <211> LENGTH: 623 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 53 Met Ala Ala Glu Ser Gly Glu Leu Ile Gly Ala Cys Glu Phe Met Lys 1 5 10 15 Asp Arg Leu Tyr Phe Ala Thr Leu Arg Asn Arg Pro Lys Ser Thr Val 20 25 30 Asn Thr His Tyr Phe Ser Ile Asp Glu Glu Leu Val Tyr Glu Asn Phe 35 40 45 Tyr Ala Asp Phe Gly Pro Leu Asn Leu Ala Met Val Tyr Arg Tyr Cys 50 55 60 Cys Lys Leu Asn Lys Lys Leu Lys Ser Tyr Ser Leu Ser Arg Lys Lys 65 70 75 80 Ile Val His Tyr Thr Cys Phe Asp Gln Arg Lys Arg Ala Asn Ala Ala 85 90 95 Phe Leu Ile Gly Ala Tyr Ala Val Ile Tyr Leu Lys Lys Thr Pro Glu 100 105 110 Glu Ala Tyr Arg Ala Leu Leu Ser Gly Ser Asn Pro Pro Tyr Leu Pro 115 120 125 Phe Arg Asp Ala Ser Phe Gly Asn Cys Thr Tyr Asn Leu Thr Ile Leu 130 135 140 Asp Cys Leu Gln Gly Ile Arg Lys Gly Leu Gln His Gly Phe Phe Asp 145 150 155 160 Phe Glu Thr Phe Asp Val Asp Glu Tyr Glu His Tyr Glu Arg Val Glu 165 170 175 Asn Gly Asp Phe Asn Trp Ile Val Pro Gly Lys Phe Leu Ala Phe Ser 180 185 190 Gly Pro His Pro Lys Ser Lys Ile Glu Asn Gly Tyr Pro Leu His Ala 195 200 205 Pro Glu Ala Tyr Phe Pro Tyr Phe Lys Lys His Asn Val Thr Ala Val 210 215 220 Val Arg Leu Asn Lys Lys Ile Tyr Glu Ala Lys Arg Phe Thr Asp Ala 225 230 235 240 Gly Phe Glu His Tyr Asp Leu Phe Phe Ile Asp Gly Ser Thr Pro Ser 245 250 255 Asp Asn Ile Val Arg Arg Phe Leu Asn Ile Cys Glu Asn Thr Glu Gly 260 265 270 Ala Ile Ala Val His Cys Lys Ala Gly Leu Gly Arg Thr Gly Thr Leu 275 280 285 Ile Ala Cys Tyr Val Met Lys His Tyr Arg Phe Thr His Ala Glu Ile 290 295 300 Ile Ala Trp Ile Arg Ile Cys Arg Pro Gly Ser Ile Ile Gly Pro Gln 305 310 315 320 Gln His Phe Leu Glu Glu Lys Gln Ala Ser Leu Trp Val Gln Gly Asp 325 330 335 Ile Phe Arg Ser Lys Leu Lys Asn Arg Pro Ser Ser Glu Gly Ser Ile 340 345 350 Asn Lys Ile Leu Ser Gly Leu Asp Asp Met Ser Ile Gly Gly Asn Leu 355 360 365 Ser Lys Thr Gln Asn Met Glu Arg Phe Gly Glu Asp Asn Leu Glu Asp 370 375 380 Asp Asp Val Glu Met Lys Asn Gly Ile Thr Gln Gly Asp Lys Leu Arg 385 390 395 400 Ala Leu Lys Ser Gln Arg Gln Pro Arg Thr Ser Pro Ser Cys Ala Phe 405 410 415 Arg Ser Asp Asp Thr Lys Gly His Pro Arg Ala Val Ser Gln Pro Phe 420 425 430 Arg Leu Ser Ser Ser Leu Gln Gly Ser Ala Val Thr Leu Lys Thr Ser 435 440 445 Lys Met Ala Leu Ser Pro Ser Ala Thr Ala Lys Arg Ile Asn Arg Thr 450 455 460 Ser Leu Ser Ser Gly Ala Thr Val Arg Ser Phe Ser Ile Asn Ser Arg 465 470 475 480 Leu Ala Ser Ser Leu Gly Asn Leu Asn Ala Ala Thr Asp Asp Pro Glu 485 490 495 Asn Lys Lys Thr Ser Ser Ser Ser Lys Ala Gly Phe Thr Ala Ser Pro 500 505 510 Phe Thr Asn Leu Leu Asn Gly Ser Ser Gln Pro Thr Thr Arg Asn Tyr 515 520 525 Pro Glu Leu Asn Asn Asn Gln Tyr Asn Arg Ser Ser Asn Ser Asn Gly 530 535 540 Gly Asn Leu Asn Ser Pro Pro Gly Pro His Ser Ala Lys Thr Glu Glu 545 550 555 560 His Thr Thr Ile Leu Arg Pro Ser Tyr Thr Gly Leu Ser Ser Ser Ser 565 570 575 Ala Arg Phe Leu Ser Arg Ser Ile Pro Val Ser Ala Gln Thr Pro Pro 580 585 590 Pro Gly Pro Gln Asn Pro Glu Cys Asn Phe Cys Ala Leu Pro Ser Gln 595 600 605 Pro Arg Leu Pro Pro Lys Lys Phe Asn Ser Ala Lys Glu Ala Phe 610 615 620 <210> SEQ ID NO 54 <211> LENGTH: 1890 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 54 ccggagcagc tgctgccagc ccgcgggcac tgaagtcctc ccggctgccg ctcgagtagc 60 cacgggcgcg atcgggacca gaagtctcct cctccatgat cactttggaa gccgggggaa 120 gactttgccc tgccctgaga gctggtctgc gtttcccagg cgcggcggcg gcggagcagc 180 agctgcagca gccgagtcca aataggagcg gccacagcca ggggcgtgtg cgccccgcgc 240 ggagcgagct cgggttcccc tcggaatgtc cccggggcgc ccggcgcgct gaccccgaag 300 ccgcctccgc cttcggcgcc tgctgcctcc ctcggccagg cttgttgttc gggactgtga 360 gcttcctggc tcctgggcag tggggaagcc cccgggggcg agtgacctca gctggccacg 420 acccagccct cccccgtgcg tatctcgctt aagatggcag cggagtcagg ggaactaatc 480 ggggcttgtg agttcatgaa agatcggtta tattttgcta ctttaaggaa tagaccaaaa 540 agcacagtaa atacccacta tttctccatc gatgaggagc tggtctatga aaatttctat 600 gcagattttg gaccgctgaa cttggcaatg gtgtacagat attgctgcaa actaaacaag 660 aaactaaaat catacagttt gtcaagaaag aaaatagtgc actacacctg ttttgaccaa 720 cggaaaagag caaatgcagc atttttgata ggtgcctatg cagtaatcta tttaaagaag 780 acaccagaag aagcctacag agcactcctg tctggctcaa acccccccta tcttccattc 840 agggatgctt cctttggaaa ttgcacttac aatctcacca ttctcgactg tttgcaggga 900 atcagaaagg gattacaaca tggatttttt gactttgaga catttgatgt ggatgaatat 960 gaacattatg agcgagttga aaatggtgac ttcaactgga ttgttccagg aaaattttta 1020 gcatttagtg gaccacatcc taaaagcaaa attgagaatg gttatcctct tcacgcccct 1080 gaagcctact ttccttattt caaaaagcat aatgtgactg cagttgtgag gctaaacaaa 1140 aagatttatg aggcaaagcg cttcacagac gctggcttcg agcactatga cctcttcttc 1200 atagatggca gcacacccag tgacaacatc gtgcgaaggt tcctgaacat ctgtgagaac 1260 accgaagggg ccatcgccgt tcactgcaaa gctggtcttg gaagaacagg gacattgata 1320 gcctgttatg taatgaaaca ctacaggttt acacatgctg aaataattgc ttggattaga 1380 atatgccggc caggctctat tataggaccc cagcagcact tcctggaaga aaaacaagca 1440 tcgttgtggg tccaaggaga cattttccga tccaaactga aaaatcgacc atccagtgaa 1500 ggaagtatta ataaaattct ttctggccta gatgatatgt ctattggtgg aaatctttca 1560 aaaacacaaa acatggaacg atttggagag gtaagttttc cctaggagat tctatcttct 1620 taaaactgat gttctgcatt tgtttctcag ttggacctat ataacatagc agtgtctttt 1680 ctctggatgc cacgagtacc aagtttttag aagtagagcc atccgtctat atagcaagaa 1740 gcagaggaaa gaaaccaatt gcccttaaaa aaaaaaagct ataatttaag gagtaaatta 1800 taaaggaggc tactctggta aggggtaata tttatagaaa ggaaacagaa aagcaaactt 1860 tctatttgaa aaaaaaaaaa aaaaaaaaaa 1890 <210> SEQ ID NO 55 <211> LENGTH: 383 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 55 Met Ala Ala Glu Ser Gly Glu Leu Ile Gly Ala Cys Glu Phe Met Lys 1 5 10 15 Asp Arg Leu Tyr Phe Ala Thr Leu Arg Asn Arg Pro Lys Ser Thr Val 20 25 30 Asn Thr His Tyr Phe Ser Ile Asp Glu Glu Leu Val Tyr Glu Asn Phe 35 40 45 Tyr Ala Asp Phe Gly Pro Leu Asn Leu Ala Met Val Tyr Arg Tyr Cys 50 55 60 Cys Lys Leu Asn Lys Lys Leu Lys Ser Tyr Ser Leu Ser Arg Lys Lys 65 70 75 80 Ile Val His Tyr Thr Cys Phe Asp Gln Arg Lys Arg Ala Asn Ala Ala 85 90 95 Phe Leu Ile Gly Ala Tyr Ala Val Ile Tyr Leu Lys Lys Thr Pro Glu 100 105 110 Glu Ala Tyr Arg Ala Leu Leu Ser Gly Ser Asn Pro Pro Tyr Leu Pro 115 120 125 Phe Arg Asp Ala Ser Phe Gly Asn Cys Thr Tyr Asn Leu Thr Ile Leu 130 135 140 Asp Cys Leu Gln Gly Ile Arg Lys Gly Leu Gln His Gly Phe Phe Asp 145 150 155 160 Phe Glu Thr Phe Asp Val Asp Glu Tyr Glu His Tyr Glu Arg Val Glu 165 170 175 Asn Gly Asp Phe Asn Trp Ile Val Pro Gly Lys Phe Leu Ala Phe Ser 180 185 190 Gly Pro His Pro Lys Ser Lys Ile Glu Asn Gly Tyr Pro Leu His Ala 195 200 205 Pro Glu Ala Tyr Phe Pro Tyr Phe Lys Lys His Asn Val Thr Ala Val 210 215 220 Val Arg Leu Asn Lys Lys Ile Tyr Glu Ala Lys Arg Phe Thr Asp Ala 225 230 235 240 Gly Phe Glu His Tyr Asp Leu Phe Phe Ile Asp Gly Ser Thr Pro Ser 245 250 255 Asp Asn Ile Val Arg Arg Phe Leu Asn Ile Cys Glu Asn Thr Glu Gly 260 265 270 Ala Ile Ala Val His Cys Lys Ala Gly Leu Gly Arg Thr Gly Thr Leu 275 280 285 Ile Ala Cys Tyr Val Met Lys His Tyr Arg Phe Thr His Ala Glu Ile 290 295 300 Ile Ala Trp Ile Arg Ile Cys Arg Pro Gly Ser Ile Ile Gly Pro Gln 305 310 315 320 Gln His Phe Leu Glu Glu Lys Gln Ala Ser Leu Trp Val Gln Gly Asp 325 330 335 Ile Phe Arg Ser Lys Leu Lys Asn Arg Pro Ser Ser Glu Gly Ser Ile 340 345 350 Asn Lys Ile Leu Ser Gly Leu Asp Asp Met Ser Ile Gly Gly Asn Leu 355 360 365 Ser Lys Thr Gln Asn Met Glu Arg Phe Gly Glu Val Ser Phe Pro 370 375 380 <210> SEQ ID NO 56 <211> LENGTH: 4624 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 cacggaacag ccctcctggg gtccccacga gccgcgtcct gctgtgcccc ggcgcctacg 60 cagcagcggc cgcggccgcg gtgggcacgc acggttaccc cgggcagctc cggccgccag 120 ctgcagcccc gtcgcctcgg ccgcgccagc cggctgcggg cacctggggg cgggctgggg 180 gcgccggccg cggcaggagg cgctgtagcg agggctgcgg cgccggtcct gcggcggccg 240 cgggaggcag cggggcaggc gctgtgggcc gggctcctcc tccggctcct gcgcgaccgc 300 ctcccgccgg gctctgccgg cgcccgccgt ccccgcagcg ccgctctgcg cccgccgccc 360 cgagcgcccg cgcggggctg gcgggagcct cggcgggcgc gcgggcgcgc ggggccatgg 420 tcgtggcccc ctgacgggcc gcggccgcct ccatgaagcg gaaaagcgag cggcggtcga 480 gctgggccgc cgcgcccccc tgctcgcggc gctgctcgtc gacctcgccg ggtgtgaaga 540 agatccgcag ctccacgcag caagacccgc gccgccggga cccccaggac gacgtgtacc 600 tggacatcac cgatcgcctt tgttttgcca ttctctacag cagaccaaag agtgcatcaa 660 atgtacatta tttcagcata gataatgaac ttgaatatga gaacttctac gcagattttg 720 gaccactcaa tctggcaatg gtttacagat attgttgcaa gatcaataag aaattaaagt 780 ccattacaat gttaaggaag aaaattgttc attttactgg ctctgatcag agaaaacaag 840 caaatgctgc cttccttgtt ggatgctaca tggttatata tttggggaga accccagaag 900 aagcatatag aatattaatc tttggagaga catcctatat tcctttcaga gatgctgcct 960 atggaagttg caatttctac attacacttc ttgactgttt tcatgcagta aagaaggcaa 1020 tgcagtatgg cttccttaat ttcaactcat ttaaccttga tgaatatgaa cactatgaaa 1080 aagcagaaaa tggagattta aattggataa taccagaccg atttattgcc ttctgtggac 1140 ctcattcaag agccagactt gaaagtggtt accaccaaca ttctcctgag acttatattc 1200 aatattttaa gaatcacaat gttactacca ttattcgtct gaataaaagg atgtatgatg 1260 ccaaacgctt tacggatgct ggcttcgatc accatgatct tttctttgcg gatggcagca 1320 cccctactga tgccattgtc aaagaattcc tagatatctg tgaaaatgct gagggtgcca 1380 ttgcagtaca ttgcaaagct ggccttggtc gcacgggcac tctgatagcc tgctacatca 1440 tgaagcatta caggatgaca gcagccgaga ccattgcgtg ggtcaggatc tgcagacctg 1500 gctcggtgat tgggcctcag cagcagtttt tggtgatgaa gcaaaccaac ctctggctgg 1560 aaggggacta ttttcgtcag aagttaaagg ggcaggagaa tggacaacac agagcagcct 1620 tctccaaact tctctctggc gttgatgaca tttccataaa tggggtcgag aatcaagatc 1680 agcaagaacc cgaaccgtac agtgatgatg acgaaatcaa tggagtgaca caaggtgata 1740 gacttcgggc cttgaaaagc agaagacaat ccaaaacaaa cgctattcct ctcacagtaa 1800 ttcttcaatc cagtgttcag agctgtaaaa catctgaacc taacatttct ggcagtgcag 1860 gcattactaa aagaaccacc agatctgctt caaggaaaag cagtgttaaa agtctctcca 1920 tttcaaggac taaaacagtc ttgcgttaag taaaaacctg tgaccagagc tgaaggaaga 1980 ctctaggact gaaaactgca acagaaatta gcacaatttg aaaacaaaac aaaattgcaa 2040 aagccttagt tgctttttcc acctaagaag ttgatcaatg gagaaaatgt ccactggagt 2100 ttgaataatg aactttgagt ttgggtgcaa gcaaatgact cagagaaggg tccagctctc 2160 aagctgaatg acaaacatgc tgttgtaaat ttagtctcag gtgtaaatac ccaagccctc 2220 tggtacccag ggagctggct ggtctgtggt gcatgtgtgt ccctgtgatg gcaatcattg 2280 tagttgctgg ccttcagaag aattgaggat ctgatggagt ttttttatgt atttattttc 2340 tgttcacctt gtgaccctgt gtcaaaattt ataaagatac aaaaggcatt actgaaatgg 2400 tactttctgt aatttgatac tatttggctt aatcatcttc acttgactat ttgtaatact 2460 gttgtaatgt taactctgtt aagtacccaa gctgcttgtc ttccaccaaa gagtgcttta 2520 ttaacaagaa tctgtgaaaa tcacatttaa acactgttgc atgttgtaag accaggtggt 2580 accttagtaa cctaaaactt gcaagagaat attaatggta gctttagaag actcaggagg 2640 agaaactgac ttcagagttg gaagatgttg caagtcgttc ctttttctgt ccttcaggga 2700 ctgaagaact gggaggctgc ccattgtttg gttgccagtc atacaaatta aaatcatatt 2760 tccttccatg aatggaagaa acacactatt ggtttttccc cttggaaaca gcaatcccaa 2820 ataatgtcgg cttacaaaaa aaaaaagtta ccactttttt agagtccttc cctgtaacat 2880 tggatttttt ttttccctta tgagatccac ctaaggccat tgacgtggcc tgcgatctca 2940 gtgacaatga tctgcttctg gatctcactg ttgcctttgg ttagggaaca caactagtaa 3000 ctctgcagag tgccttctcc cgcagcccta ctggaacaca gcagagtctg tgccatgaag 3060 cagttacaga aacagaattg atgtgctgcc aaaaaaaaaa aaaaaatggg gcccgaaata 3120 aaagaatata tagtactcac ctcagttcct tccataagaa gtgggtggtt taatgattgt 3180 taagccattt ttgcctgtgc cgggagcatg gagggctgag atgtcgacag gcagtgggaa 3240 acaaatgccc tcctaagcca caaggcgtgc gccagattag taggcaactc cattttaaga 3300 agctgccttt ttcacaaaac tggaagaaat aaaagcggtt ggaataaaca agttaaaagt 3360 ctttaatgca aaaagtaatt gaaaggcagt gcctccattt tggtgtactt tcttggaaga 3420 aagtataaaa ttgaccggca tcatgagaga cggaagatgc cgtgttctca gccaaacaag 3480 caactctttc cccgccaggc actgtcgggt ggggtcaggc cagcttttaa acactgggga 3540 ctggatcaca gaaaaacagt ggttttctgt ccctggaaat gaataggcac aaagacccac 3600 ttggctgtgg gcagactact cttcaataag atttgggtgg gaggaggaac attccttttg 3660 ctattttgag ctgagacaat ataaatattc aaactgtgcc atgcataaag cattgaattc 3720 tcagggcacc tcttcttccc cttacccctt ttaaggccat cccctccatt aataataatc 3780 caggtagttg tgaaaatcgt gcttctatct gatcccttct tagtttggct tttcatccca 3840 tcagaacaag taaacgtagg cgccacagct cttgtgagta ctgtctccct cacggtgaat 3900 gagcctcctg gtgtttcgtc caagaaaaga aagggtgtca ctggaaccac agcccttttt 3960 cattttataa actgcctctt catgttgcct gctcaagttt ccacctagaa ttgctatcac 4020 tgtggctctt tctaaaaatc tttctattta actggttcac tgaaattagt catagaaaac 4080 ttgtgatttg gtgaagaggc attccttgta ataaccaaat gacttgggat ggtgtgcata 4140 gcaagggcag tgttacactt atgaggactg tctctagcat ccaggaagtc tctgggtctg 4200 agggatggaa agttcttcct gctatgaatg agagtggact cttcccctca cccccaactg 4260 aaaccacaaa caaccagaat cttctggaat tctgacttag agtcgttgtt atagaagacc 4320 ttgttgctat ggaacatgaa actgtgtgtc agatggagag atccccttaa cctaagagcc 4380 ttaaatagcc ctgaaagtac actgggacgg tttgcgatgg aattaaaatt ggaagtgaat 4440 atttttaggt gctcttgaag ctttctgggg actcaaaatt atcaaaagtc agggacagtc 4500 cggaggaaga gcgtctgcaa aactgggttc ctagaagtat agacggactt agctttttgt 4560 agaatttggt gaggagcagc gcctcgtgag agcagaatgg cctggcgtgg ccagtgcttc 4620 ccgg 4624 <210> SEQ ID NO 57 <211> LENGTH: 498 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 57 Met Lys Arg Lys Ser Glu Arg Arg Ser Ser Trp Ala Ala Ala Pro Pro 1 5 10 15 Cys Ser Arg Arg Cys Ser Ser Thr Ser Pro Gly Val Lys Lys Ile Arg 20 25 30 Ser Ser Thr Gln Gln Asp Pro Arg Arg Arg Asp Pro Gln Asp Asp Val 35 40 45 Tyr Leu Asp Ile Thr Asp Arg Leu Cys Phe Ala Ile Leu Tyr Ser Arg 50 55 60 Pro Lys Ser Ala Ser Asn Val His Tyr Phe Ser Ile Asp Asn Glu Leu 65 70 75 80 Glu Tyr Glu Asn Phe Tyr Ala Asp Phe Gly Pro Leu Asn Leu Ala Met 85 90 95 Val Tyr Arg Tyr Cys Cys Lys Ile Asn Lys Lys Leu Lys Ser Ile Thr 100 105 110 Met Leu Arg Lys Lys Ile Val His Phe Thr Gly Ser Asp Gln Arg Lys 115 120 125 Gln Ala Asn Ala Ala Phe Leu Val Gly Cys Tyr Met Val Ile Tyr Leu 130 135 140 Gly Arg Thr Pro Glu Glu Ala Tyr Arg Ile Leu Ile Phe Gly Glu Thr 145 150 155 160 Ser Tyr Ile Pro Phe Arg Asp Ala Ala Tyr Gly Ser Cys Asn Phe Tyr 165 170 175 Ile Thr Leu Leu Asp Cys Phe His Ala Val Lys Lys Ala Met Gln Tyr 180 185 190 Gly Phe Leu Asn Phe Asn Ser Phe Asn Leu Asp Glu Tyr Glu His Tyr 195 200 205 Glu Lys Ala Glu Asn Gly Asp Leu Asn Trp Ile Ile Pro Asp Arg Phe 210 215 220 Ile Ala Phe Cys Gly Pro His Ser Arg Ala Arg Leu Glu Ser Gly Tyr 225 230 235 240 His Gln His Ser Pro Glu Thr Tyr Ile Gln Tyr Phe Lys Asn His Asn 245 250 255 Val Thr Thr Ile Ile Arg Leu Asn Lys Arg Met Tyr Asp Ala Lys Arg 260 265 270 Phe Thr Asp Ala Gly Phe Asp His His Asp Leu Phe Phe Ala Asp Gly 275 280 285 Ser Thr Pro Thr Asp Ala Ile Val Lys Glu Phe Leu Asp Ile Cys Glu 290 295 300 Asn Ala Glu Gly Ala Ile Ala Val His Cys Lys Ala Gly Leu Gly Arg 305 310 315 320 Thr Gly Thr Leu Ile Ala Cys Tyr Ile Met Lys His Tyr Arg Met Thr 325 330 335 Ala Ala Glu Thr Ile Ala Trp Val Arg Ile Cys Arg Pro Gly Ser Val 340 345 350 Ile Gly Pro Gln Gln Gln Phe Leu Val Met Lys Gln Thr Asn Leu Trp 355 360 365 Leu Glu Gly Asp Tyr Phe Arg Gln Lys Leu Lys Gly Gln Glu Asn Gly 370 375 380 Gln His Arg Ala Ala Phe Ser Lys Leu Leu Ser Gly Val Asp Asp Ile 385 390 395 400 Ser Ile Asn Gly Val Glu Asn Gln Asp Gln Gln Glu Pro Glu Pro Tyr 405 410 415 Ser Asp Asp Asp Glu Ile Asn Gly Val Thr Gln Gly Asp Arg Leu Arg 420 425 430 Ala Leu Lys Ser Arg Arg Gln Ser Lys Thr Asn Ala Ile Pro Leu Thr 435 440 445 Val Ile Leu Gln Ser Ser Val Gln Ser Cys Lys Thr Ser Glu Pro Asn 450 455 460 Ile Ser Gly Ser Ala Gly Ile Thr Lys Arg Thr Thr Arg Ser Ala Ser 465 470 475 480 Arg Lys Ser Ser Val Lys Ser Leu Ser Ile Ser Arg Thr Lys Thr Val 485 490 495 Leu Arg <210> SEQ ID NO 58 <211> LENGTH: 4960 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 58 cacggaacag ccctcctggg gtccccacga gccgcgtcct gctgtgcccc ggcgcctacg 60 cagcagcggc cgcggccgcg gtgggcacgc acggttaccc cgggcagctc cggccgccag 120 ctgcagcccc gtcgcctcgg ccgcgccagc cggctgcggg cacctggggg cgggctgggg 180 gcgccggccg cggcaggagg cgctgtagcg agggctgcgg cgccggtcct gcggcggccg 240 cgggaggcag cggggcaggc gctgtgggcc gggctcctcc tccggctcct gcgcgaccgc 300 ctcccgccgg gctctgccgg cgcccgccgt ccccgcagcg ccgctctgcg cccgccgccc 360 cgagcgcccg cgcggggctg gcgggagcct cggcgggcgc gcgggcgcgc ggggccatgg 420 tcgtggcccc ctgacgggcc gcggccgcct ccatgaagcg gaaaagcgag cggcggtcga 480 gctgggccgc cgcgcccccc tgctcgcggc gctgctcgtc gacctcgccg ggtgtgaaga 540 agatccgcag ctccacgcag caagacccgc gccgccggga cccccaggac gacgtgtacc 600 tggacatcac cgatcgcctt tgttttgcca ttctctacag cagaccaaag agtgcatcaa 660 atgtacatta tttcagcata gataatgaac ttgaatatga gaacttctac gcagattttg 720 gaccactcaa tctggcaatg gtttacagat attgttgcaa gatcaataag aaattaaagt 780 ccattacaat gttaaggaag aaaattgttc attttactgg ctctgatcag agaaaacaag 840 caaatgctgc cttccttgtt ggatgctaca tggttatata tttggggaga accccagaag 900 aagcatatag aatattaatc tttggagaga catcctatat tcctttcaga gatgctgcct 960 atggaagttg caatttctac attacacttc ttgactgttt tcatgcagta aagaaggcaa 1020 tgcagtatgg cttccttaat ttcaactcat ttaaccttga tgaatatgaa cactatgaaa 1080 aagcagaaaa tggagattta aattggataa taccagaccg atttattgcc ttctgtggac 1140 ctcattcaag agccagactt gaaagtggtt accaccaaca ttctcctgag acttatattc 1200 aatattttaa gaatcacaat gttactacca ttattcgtct gaataaaagg atgtatgatg 1260 ccaaacgctt tacggatgct ggcttcgatc accatgatct tttctttgcg gatggcagca 1320 cccctactga tgccattgtc aaagaattcc tagatatctg tgaaaatgct gagggtgcca 1380 ttgcagtaca ttgcaaagct ggccttggtc gcacgggcac tctgatagcc tgctacatca 1440 tgaagcatta caggatgaca gcagccgaga ccattgcgtg ggtcaggatc tgcagacctg 1500 gctcggtgat tgggcctcag cagcagtttt tggtgatgaa gcaaaccaac ctctggctgg 1560 aaggggacta ttttcgtcag aagttaaagg ggcaggagaa tggacaacac agagcagcct 1620 tctccaaact tctctctggc gttgatgaca tttccataaa tggggtcgag aatcaagatc 1680 agcaagaacc cgaaccgtac agtgatgatg acgaaatcaa tggagtgaca caaggtgata 1740 gacttcgggc cttgaaaagc agaagacaat ccaaaacaaa cgctattcct ctcaccgatg 1800 gttggctgtc ccaggctgtc acctttctag accggcttct gatctggctc gggatccaca 1860 aggactagac ctgcggggaa ggtctctcct ggacacgccc gttgcccact gcaagttctc 1920 tccaggtgca attgaagcct ctcagcagcg gaggccgcca tgtggagaga gcaggcaggc 1980 ccactgctgc tgagaacagg gcaggcacgg gcagctcctg ttctgccttt cccagcttcg 2040 gagacgcagg ctcagctgct ccgaagcacc tgccagcacc gcacagtaca gtttcagagg 2100 acagcagtct ccttcccgtg aagctcccat gtgctggaat ggcatggact tgctgatcaa 2160 cagaaggaaa tggtctgaag tctgaccagc acaaggaagg aggctggctg gctcagaggg 2220 gcccaccttg cgtggaatga aaacgccaaa ggctcatgag caacattagg ctagaggggt 2280 cttgttcaaa gcatccaact ctgacttcgg aggcattccc agccggcagc agtgtgtcca 2340 gcctgcctct tcccaggctg gtctgacatg cagcttaggc tttcatccca agttaggtac 2400 tgacccctcc ctcttgggca gcacctccct ttttaaaaaa attttttttt cttccaaaga 2460 cagagtcttg ctcttgttgt ccaggctgga gtgcagtggc gcgatctagg ctcactgcaa 2520 cctccttctc ccaggttcaa gcgactctcc tgcctcagcc tcctgagtag ctgggattat 2580 aggcgtctgc caccacgccc ggctaatttc tgtattttta gtagagacag ggtttcacca 2640 tgttggccag gctggtctcg aactcctgac ctcaagtgat ctgcctgcct tggcctccca 2700 aagtgctggg attacaggtg tcagccaccg cacccagcca agcaccccta tctctagagg 2760 atctggcccc ccagcccagt tactgcaggg cagctttccc cacctggtga caggctgtgc 2820 gcagcagccc caggacctca ccctgagctg agtcttcagg agccgccctg gtggcacaac 2880 tcagacaccc ctgaggccta gcagtcaact cctgattcag acatgatcca gtccagcctg 2940 ggcttggcta taaccagctc aaacttgctt gacctccact tttcaggaga cttggggacg 3000 acagccctca tcggcgtctt tcatggggtt aatctgcttg agtctaagtc gccagccaga 3060 aacgtggtgc ccagggtgcc ctgcctcagg acatgtccac acccacgtca caagcacctg 3120 aggagtccgg ccggggcact gtggtccaaa aggtcctgcc gcctccgcat ctgactgtcc 3180 caacggcatg ctggtgacac ccccctgccc ttcgcttctg tcctccctgg cttctctggg 3240 gcacttgggg ctatgtacaa cctggcacga tccagaaagg gtgcaaacaa aatgcctaca 3300 tccaggcaca cgaccaagtc agcgagagct agccctggta agcaaacata gcccattaca 3360 ggttcagaac gtgcaccggg ttccccaaaa ctgtcttcaa ccacatgact caacagctct 3420 atgggatagg aactgtcagt gtttttgcaa ctgcaacatt aaaccaagtg ctgtgggctt 3480 ttcaagtatt attcacaaca ctaaaggaaa gtttcttcaa agggctctct ggctaatctt 3540 caaagccgca gttaggcaaa atgacagtgt gacagcttca aagccactga ctcatgacac 3600 agccctgatg ttgtaccggc taggttcaga tttcagaaat cagggcactt gcatccattg 3660 ccttttccag gaaagggaag aaaacactca gttgataaac cttagtactc agataataaa 3720 taagagacca aaagtaggct atcacccaaa gcaaacatcc ttaactgacc ctaacgtgta 3780 tggattcaac tttgattatt caacaaaatc atgaccgact gctgtggcct ggagtaacca 3840 aaggactgtt ttctctacac aaagtcagga gcgaatacca acctttattt gcacttgggt 3900 tccagttcaa agccacctta gacagtgtgg caaagtggga aaaagcacag atcctgggac 3960 caaggttcag attccatctc aagcgagcat atgaactgtg tgacaacagg cagacagtac 4020 ctctgtgtct atgagaaagc ggggagagca acaccccagc ttctagcagc tctacagctg 4080 cctggacctg caggccctcc taggcccact tcctccccag cacagtgtgt gttcccgggc 4140 gtgtgtggct ctgggtccag ctctgttcag ggtgggactc caggtgaatt actgaacctc 4200 tgaggtgtac ccccaacccc aaactttcac caaaagcaat aaagaggaac tctagaactg 4260 gagccaggac taagtgagaa aaactgctta taagtgctta ataaatacta gttatttaca 4320 acttttgctc aagccgaggg cagaggcctt tgtacgcagc tgccgaactc tgactctagt 4380 tctgcggaag aaaaggatgc ggtatttgct tttgccatga tccctttcca tttgattggc 4440 aggttaaata acatggtttt tgaagtcaca tacttaatat tcttcctaaa aaccacccaa 4500 acactagatg tgtgtgtgca cacacacaga aaccacgggg tagtttaaat caccattaaa 4560 aatcaacgct ttctctgatt ctgtgtcaca gagtggtggc cagtggctac aatttttaaa 4620 tgattggtta agtgaaaacc agaactcaaa atattccagg agagaagata acatttacaa 4680 gtaaacagta agtgcaattg tattttaatt tcttggtctc cgaaaactca gctgtgactg 4740 ctttccatta acagttccag ctctatgtgt ttcctctaac gctaaaggca cagcccccgg 4800 gaatctactg cttcctaaga gtctccatgg agtctatttt acaacctcct ttccctccat 4860 gcttccgcgg aggagtctat actatctcta tatacacatt ttaaacatta ttcttcattt 4920 gaaattcctt caataaaaac acagtcacca ttaaaaaaaa 4960 <210> SEQ ID NO 59 <211> LENGTH: 471 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 Met Lys Arg Lys Ser Glu Arg Arg Ser Ser Trp Ala Ala Ala Pro Pro 1 5 10 15 Cys Ser Arg Arg Cys Ser Ser Thr Ser Pro Gly Val Lys Lys Ile Arg 20 25 30 Ser Ser Thr Gln Gln Asp Pro Arg Arg Arg Asp Pro Gln Asp Asp Val 35 40 45 Tyr Leu Asp Ile Thr Asp Arg Leu Cys Phe Ala Ile Leu Tyr Ser Arg 50 55 60 Pro Lys Ser Ala Ser Asn Val His Tyr Phe Ser Ile Asp Asn Glu Leu 65 70 75 80 Glu Tyr Glu Asn Phe Tyr Ala Asp Phe Gly Pro Leu Asn Leu Ala Met 85 90 95 Val Tyr Arg Tyr Cys Cys Lys Ile Asn Lys Lys Leu Lys Ser Ile Thr 100 105 110 Met Leu Arg Lys Lys Ile Val His Phe Thr Gly Ser Asp Gln Arg Lys 115 120 125 Gln Ala Asn Ala Ala Phe Leu Val Gly Cys Tyr Met Val Ile Tyr Leu 130 135 140 Gly Arg Thr Pro Glu Glu Ala Tyr Arg Ile Leu Ile Phe Gly Glu Thr 145 150 155 160 Ser Tyr Ile Pro Phe Arg Asp Ala Ala Tyr Gly Ser Cys Asn Phe Tyr 165 170 175 Ile Thr Leu Leu Asp Cys Phe His Ala Val Lys Lys Ala Met Gln Tyr 180 185 190 Gly Phe Leu Asn Phe Asn Ser Phe Asn Leu Asp Glu Tyr Glu His Tyr 195 200 205 Glu Lys Ala Glu Asn Gly Asp Leu Asn Trp Ile Ile Pro Asp Arg Phe 210 215 220 Ile Ala Phe Cys Gly Pro His Ser Arg Ala Arg Leu Glu Ser Gly Tyr 225 230 235 240 His Gln His Ser Pro Glu Thr Tyr Ile Gln Tyr Phe Lys Asn His Asn 245 250 255 Val Thr Thr Ile Ile Arg Leu Asn Lys Arg Met Tyr Asp Ala Lys Arg 260 265 270 Phe Thr Asp Ala Gly Phe Asp His His Asp Leu Phe Phe Ala Asp Gly 275 280 285 Ser Thr Pro Thr Asp Ala Ile Val Lys Glu Phe Leu Asp Ile Cys Glu 290 295 300 Asn Ala Glu Gly Ala Ile Ala Val His Cys Lys Ala Gly Leu Gly Arg 305 310 315 320 Thr Gly Thr Leu Ile Ala Cys Tyr Ile Met Lys His Tyr Arg Met Thr 325 330 335 Ala Ala Glu Thr Ile Ala Trp Val Arg Ile Cys Arg Pro Gly Ser Val 340 345 350 Ile Gly Pro Gln Gln Gln Phe Leu Val Met Lys Gln Thr Asn Leu Trp 355 360 365 Leu Glu Gly Asp Tyr Phe Arg Gln Lys Leu Lys Gly Gln Glu Asn Gly 370 375 380 Gln His Arg Ala Ala Phe Ser Lys Leu Leu Ser Gly Val Asp Asp Ile 385 390 395 400 Ser Ile Asn Gly Val Glu Asn Gln Asp Gln Gln Glu Pro Glu Pro Tyr 405 410 415 Ser Asp Asp Asp Glu Ile Asn Gly Val Thr Gln Gly Asp Arg Leu Arg 420 425 430 Ala Leu Lys Ser Arg Arg Gln Ser Lys Thr Asn Ala Ile Pro Leu Thr 435 440 445 Asp Gly Trp Leu Ser Gln Ala Val Thr Phe Leu Asp Arg Leu Leu Ile 450 455 460 Trp Leu Gly Ile His Lys Asp 465 470 <210> SEQ ID NO 60 <211> LENGTH: 2646 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 2300 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 60 atgaagcgga aaagcgagcg gcggtcgagc tgggccgccg cgcccccctg ctcgcggcgc 60 tgctcgtcga cctcgccggg tgtgaagaag atccgcagct ccacgcagca agacccgcgc 120 cgccgggacc cccaggacga cgtgtacctg gacatcaccg atcgcctttg ttttgccatt 180 ctctacagca gaccaaagag tgcatcaaat gtacattatt tcagcataga taatgaactt 240 gaatatgaga acttctacgc agattttgga ccactcaatc tggcaatggt ttacagatat 300 tgttgcaaga tcaataagaa attaaagtcc attacaatgt taaggaagaa aattgttcat 360 tttactggct ctgatcagag aaaacaagca aatgctgcct tccttgttgg atgctacatg 420 gttatatatt tggggagaac cccagaagaa gcatatagaa tattaatctt tggagagaca 480 tcctatattc ctttcagaga tgctgcctat ggaagttgca atttctacat tacacttctt 540 gactgttttc atgcagtaaa gaaggcaatg cagtatggct tccttaattt caactcattt 600 aaccttgatg aatatgaaca ctatgaaaaa gcagaaaatg gagatttaaa ttggataata 660 ccagaccgat ttattgcctt ctgtggacct cattcaagag ccagacttga aagtggttac 720 caccaacatt ctcctgagac ttatattcaa tattttaaga atcacaatgt tactaccatt 780 attcgtctga ataaaaggat gtatgatgcc aaacgcttta cggatgctgg cttcgatcac 840 catgatcttt tctttgcgga tggcagcacc cctactgatg ccattgtcaa agaattccta 900 gatatctgtg aaaatgctga gggtgccatt gcagtacatt gcaaagctgg ccttggtcgc 960 acgggcactc tgatagcctg ctacatcatg aagcattaca ggatgacagc agccgagacc 1020 attgcgtggg tcaggatctg cagacctggc tcggtgattg ggcctcagca gcagtttttg 1080 gtgatgaagc aaaccaacct ctggctggaa ggggactatt ttcgtcagaa gttaaagggg 1140 caggagaatg gacaacacag agcagccttc tccaaacttc tctctggcgt tgatgacatt 1200 tccataaatg gggtcgagaa tcaagatcag caagaacccg aaccgtacag tgatgatgac 1260 gaaatcaatg gagtgacaca aggtgataga cttcgggcct tgaaaagcag aagacaatcc 1320 aaaacaaacg ctattcctct cactctctcc atttcaagga ctaaaacagt cttgcgttaa 1380 gtaaaaacct gtgaccagag ctgaaggaag actctaggac tgaaaactgc aacagaaatt 1440 agcacaattt gaaaacaaaa caaaattgca aaagccttag ttgctttttc cacctaagaa 1500 gttgatcaat ggagaaaatg tccactggag tttgaataat gaactttgag tttgggtgca 1560 agcaaatgac tcagagaagg gtccagctct caagctgaat gacaaacatg ctgttgtaaa 1620 tttagtctca ggtgtaaata cccaagccct ctggtaccca gggagctggc tggtctgtgg 1680 tgcatgtgtg tccctgtgat ggcaatcatt gtagttgctg gccttcagaa gaattgagga 1740 tctgatggag gttttttatg tatttatttt ctgttcacct tgtgaccctg tgtcaaaatt 1800 tataaagata caaaaggcat tactgaaatg gtactttctg taatttgata ctatttggct 1860 taatcatctt cacttgacta tttgtaatac tgttgtaatg ttaactctgt taagtaccca 1920 agctgcttgt cttccaccaa agagtgcttt attaacaaga atctgtgaaa atcacattta 1980 aacactgttg catgttgtaa gaccaggtgg taccttagta acctaaaact tgcaagagaa 2040 tattaatggt agctttagaa gactcaggag gagaaactga cttcagagtt ggaagatgtt 2100 gcaagtcgtt cctttttctg tccttcaggg actgaagaac tgggaggctg cccattgttt 2160 ggttgccagt catacaaatt aaaatcatat ttccttccat gaatggaaga aacacactat 2220 tggtttttcc ccttggaaac agcaatccca aataatgtcg gcttacaaaa aaaaaagtta 2280 ccactttttt agagtccttn ccctgtaaca ttggattttt ttttccctta tgagatccac 2340 ctaaggccat tgacgtggcc tgcgatctca gtgacaatga tctgctttct ggatctcact 2400 gttgcctttg gttagggaac acagagtgct tctcccgcag ccctactgga acacagcaga 2460 gtctgtgcca tgaagcagtt acagaaacag aattgatgtg ctgctaaaaa aaaaaaaaaa 2520 aatggggccc gggggggcgt ccgccggccc tgcgggccgc cggtgaaata ccactactct 2580 gatcgttttt tcactgaccc ggtgaggcgg gggggcgagc cccgaggggc tctcgcttct 2640 ggcgcg 2646 <210> SEQ ID NO 61 <211> LENGTH: 459 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 61 Met Lys Arg Lys Ser Glu Arg Arg Ser Ser Trp Ala Ala Ala Pro Pro 1 5 10 15 Cys Ser Arg Arg Cys Ser Ser Thr Ser Pro Gly Val Lys Lys Ile Arg 20 25 30 Ser Ser Thr Gln Gln Asp Pro Arg Arg Arg Asp Pro Gln Asp Asp Val 35 40 45 Tyr Leu Asp Ile Thr Asp Arg Leu Cys Phe Ala Ile Leu Tyr Ser Arg 50 55 60 Pro Lys Ser Ala Ser Asn Val His Tyr Phe Ser Ile Asp Asn Glu Leu 65 70 75 80 Glu Tyr Glu Asn Phe Tyr Ala Asp Phe Gly Pro Leu Asn Leu Ala Met 85 90 95 Val Tyr Arg Tyr Cys Cys Lys Ile Asn Lys Lys Leu Lys Ser Ile Thr 100 105 110 Met Leu Arg Lys Lys Ile Val His Phe Thr Gly Ser Asp Gln Arg Lys 115 120 125 Gln Ala Asn Ala Ala Phe Leu Val Gly Cys Tyr Met Val Ile Tyr Leu 130 135 140 Gly Arg Thr Pro Glu Glu Ala Tyr Arg Ile Leu Ile Phe Gly Glu Thr 145 150 155 160 Ser Tyr Ile Pro Phe Arg Asp Ala Ala Tyr Gly Ser Cys Asn Phe Tyr 165 170 175 Ile Thr Leu Leu Asp Cys Phe His Ala Val Lys Lys Ala Met Gln Tyr 180 185 190 Gly Phe Leu Asn Phe Asn Ser Phe Asn Leu Asp Glu Tyr Glu His Tyr 195 200 205 Glu Lys Ala Glu Asn Gly Asp Leu Asn Trp Ile Ile Pro Asp Arg Phe 210 215 220 Ile Ala Phe Cys Gly Pro His Ser Arg Ala Arg Leu Glu Ser Gly Tyr 225 230 235 240 His Gln His Ser Pro Glu Thr Tyr Ile Gln Tyr Phe Lys Asn His Asn 245 250 255 Val Thr Thr Ile Ile Arg Leu Asn Lys Arg Met Tyr Asp Ala Lys Arg 260 265 270 Phe Thr Asp Ala Gly Phe Asp His His Asp Leu Phe Phe Ala Asp Gly 275 280 285 Ser Thr Pro Thr Asp Ala Ile Val Lys Glu Phe Leu Asp Ile Cys Glu 290 295 300 Asn Ala Glu Gly Ala Ile Ala Val His Cys Lys Ala Gly Leu Gly Arg 305 310 315 320 Thr Gly Thr Leu Ile Ala Cys Tyr Ile Met Lys His Tyr Arg Met Thr 325 330 335 Ala Ala Glu Thr Ile Ala Trp Val Arg Ile Cys Arg Pro Gly Ser Val 340 345 350 Ile Gly Pro Gln Gln Gln Phe Leu Val Met Lys Gln Thr Asn Leu Trp 355 360 365 Leu Glu Gly Asp Tyr Phe Arg Gln Lys Leu Lys Gly Gln Glu Asn Gly 370 375 380 Gln His Arg Ala Ala Phe Ser Lys Leu Leu Ser Gly Val Asp Asp Ile 385 390 395 400 Ser Ile Asn Gly Val Glu Asn Gln Asp Gln Gln Glu Pro Glu Pro Tyr 405 410 415 Ser Asp Asp Asp Glu Ile Asn Gly Val Thr Gln Gly Asp Arg Leu Arg 420 425 430 Ala Leu Lys Ser Arg Arg Gln Ser Lys Thr Asn Ala Ile Pro Leu Thr 435 440 445 Leu Ser Ile Ser Arg Thr Lys Thr Val Leu Arg 450 455 <210> SEQ ID NO 62 <211> LENGTH: 2160 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 62 gaccagaccg gcccccccga gactatagcc ttcactttcc ctcggtccac catggagccc 60 ttgtgtccac tcctgctggt gggttttagc ttgccgctcg ccagggctct caggggcaac 120 gagaccactg ccgacagcaa cgagacaacc acgacctcag gccctccgga cccgggcgcc 180 tcccagccgc tgctggcctg gctgctactg ccgctgctgc tcctcctcct cgtgctcctt 240 ctcgccgcct acttcttcag gttcaggaag cagaggaaag ctgtggtcag caccagcgac 300 aagaagatgc ccaacggaat cttggaggag caagagcagc aaagggtgat gctgctcagc 360 aggtcaccct cagggcccaa gaagtatttt cccatccccg tggagcacct ggaggaggag 420 atccgtatca gatccgccga cgactgcaag cagtttcggg aggagttcaa ctcattgcca 480 tctggacaca tacaaggaac ttttgaactg gcaaataaag aagaaaacag agaaaaaaac 540 agatatccca acatccttcc caatgaccat tctagggtga ttctgagcca actggatgga 600 attccctgtt cagactacat caatgcttcc tacatagatg gttacaaaga gaagaataaa 660 ttcatagcag ctcaaggtcc caaacaggaa acggttaacg acttctggag aatggtctgg 720 gagcaaaagt ctgcgaccat cgtcatgtta acaaacttga aagaaaggaa agaggaaaag 780 tgccatcagt actggcccga ccaaggctgc tggacctatg gaaacatccg ggtgtgcgtg 840 gaggactgcg tggttttggt cgactacacc atccggaagt tctgcataca gccacagctc 900 cccgacggct gcaaagcccc caggctggtc tcacagctgc acttcaccag ctggcccgac 960 ttcggagtgc cttttacccc cattgggatg ctgaagttcc tcaagaaagt aaagacgctc 1020 aaccccgtgc acgctgggcc catcgtggtc cactgtagcg cgggcgtggg ccggacgggc 1080 accttcattg tgatcgatgc catgatggcc atgatgcacg cggagcagaa ggtggatgtg 1140 tttgaatttg tgtctcgaat ccgtaatcag cgccctcaga tggttcaaac ggatatgcag 1200 tacacgttca tctaccaagc cttactcgag tactacctct acggggacac agagctggac 1260 gtgtcctccc tggagaagca cctgcagacc atgcacggca ccaccaccca cttcgacaag 1320 atcgggctgg aggaggagtt caggaaattg acaaatgtcc ggatcatgaa ggagaacatg 1380 aggacgggca acttgccggc aaacatgaag aaggccaggg tcatccagat catcccgtat 1440 gacttcaacc gagtgatcct ttccatgaaa aggggtcaag aatacacaga ctacatcaac 1500 gcatccttca tagacggcta ccgacagaag gactatttca tcgccaccca ggggccactg 1560 gcacacacgg ttgaggactt ctggaggatg atctgggaat ggaaatccca cactatcgtg 1620 atgctgacgg aggtgcagga gagagagcag gataaatgct accagtattg gccaaccgag 1680 ggctcagtta ctcatggaga aataacgatt gagataaaga atgataccct ttcagaagcc 1740 atcagtatac gagactttct ggtcactctc aatcagcccc aggcccgcca ggaggagcag 1800 gtccgagtag tgcgccagtt tcacttccac ggctggcctg agatcgggat tcccgccgag 1860 ggcaaaggca tgattgacct catcgcagcc gtgcagaagc agcagcagca gacaggcaac 1920 caccccatca ccgtgcactg cagtgccgga gctgggcgaa caggtacatt catagccctc 1980 agcaacattt tggagcgagt aaaagccgag ggacttttag atgtatttca agctgtgaag 2040 agtttacgac ttcagagacc acatatggtg caaaccctgg aacagtatga attctgctac 2100 aaagtggtac aagattttat tgatatattt tctgattatg ctaatttcaa atgaagattc 2160 <210> SEQ ID NO 63 <211> LENGTH: 700 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 Met Glu Pro Leu Cys Pro Leu Leu Leu Val Gly Phe Ser Leu Pro Leu 1 5 10 15 Ala Arg Ala Leu Arg Gly Asn Glu Thr Thr Ala Asp Ser Asn Glu Thr 20 25 30 Thr Thr Thr Ser Gly Pro Pro Asp Pro Gly Ala Ser Gln Pro Leu Leu 35 40 45 Ala Trp Leu Leu Leu Pro Leu Leu Leu Leu Leu Leu Val Leu Leu Leu 50 55 60 Ala Ala Tyr Phe Phe Arg Phe Arg Lys Gln Arg Lys Ala Val Val Ser 65 70 75 80 Thr Ser Asp Lys Lys Met Pro Asn Gly Ile Leu Glu Glu Gln Glu Gln 85 90 95 Gln Arg Val Met Leu Leu Ser Arg Ser Pro Ser Gly Pro Lys Lys Tyr 100 105 110 Phe Pro Ile Pro Val Glu His Leu Glu Glu Glu Ile Arg Ile Arg Ser 115 120 125 Ala Asp Asp Cys Lys Gln Phe Arg Glu Glu Phe Asn Ser Leu Pro Ser 130 135 140 Gly His Ile Gln Gly Thr Phe Glu Leu Ala Asn Lys Glu Glu Asn Arg 145 150 155 160 Glu Lys Asn Arg Tyr Pro Asn Ile Leu Pro Asn Asp His Ser Arg Val 165 170 175 Ile Leu Ser Gln Leu Asp Gly Ile Pro Cys Ser Asp Tyr Ile Asn Ala 180 185 190 Ser Tyr Ile Asp Gly Tyr Lys Glu Lys Asn Lys Phe Ile Ala Ala Gln 195 200 205 Gly Pro Lys Gln Glu Thr Val Asn Asp Phe Trp Arg Met Val Trp Glu 210 215 220 Gln Lys Ser Ala Thr Ile Val Met Leu Thr Asn Leu Lys Glu Arg Lys 225 230 235 240 Glu Glu Lys Cys His Gln Tyr Trp Pro Asp Gln Gly Cys Trp Thr Tyr 245 250 255 Gly Asn Ile Arg Val Cys Val Glu Asp Cys Val Val Leu Val Asp Tyr 260 265 270 Thr Ile Arg Lys Phe Cys Ile Gln Pro Gln Leu Pro Asp Gly Cys Lys 275 280 285 Ala Pro Arg Leu Val Ser Gln Leu His Phe Thr Ser Trp Pro Asp Phe 290 295 300 Gly Val Pro Phe Thr Pro Ile Gly Met Leu Lys Phe Leu Lys Lys Val 305 310 315 320 Lys Thr Leu Asn Pro Val His Ala Gly Pro Ile Val Val His Cys Ser 325 330 335 Ala Gly Val Gly Arg Thr Gly Thr Phe Ile Val Ile Asp Ala Met Met 340 345 350 Ala Met Met His Ala Glu Gln Lys Val Asp Val Phe Glu Phe Val Ser 355 360 365 Arg Ile Arg Asn Gln Arg Pro Gln Met Val Gln Thr Asp Met Gln Tyr 370 375 380 Thr Phe Ile Tyr Gln Ala Leu Leu Glu Tyr Tyr Leu Tyr Gly Asp Thr 385 390 395 400 Glu Leu Asp Val Ser Ser Leu Glu Lys His Leu Gln Thr Met His Gly 405 410 415 Thr Thr Thr His Phe Asp Lys Ile Gly Leu Glu Glu Glu Phe Arg Lys 420 425 430 Leu Thr Asn Val Arg Ile Met Lys Glu Asn Met Arg Thr Gly Asn Leu 435 440 445 Pro Ala Asn Met Lys Lys Ala Arg Val Ile Gln Ile Ile Pro Tyr Asp 450 455 460 Phe Asn Arg Val Ile Leu Ser Met Lys Arg Gly Gln Glu Tyr Thr Asp 465 470 475 480 Tyr Ile Asn Ala Ser Phe Ile Asp Gly Tyr Arg Gln Lys Asp Tyr Phe 485 490 495 Ile Ala Thr Gln Gly Pro Leu Ala His Thr Val Glu Asp Phe Trp Arg 500 505 510 Met Ile Trp Glu Trp Lys Ser His Thr Ile Val Met Leu Thr Glu Val 515 520 525 Gln Glu Arg Glu Gln Asp Lys Cys Tyr Gln Tyr Trp Pro Thr Glu Gly 530 535 540 Ser Val Thr His Gly Glu Ile Thr Ile Glu Ile Lys Asn Asp Thr Leu 545 550 555 560 Ser Glu Ala Ile Ser Ile Arg Asp Phe Leu Val Thr Leu Asn Gln Pro 565 570 575 Gln Ala Arg Gln Glu Glu Gln Val Arg Val Val Arg Gln Phe His Phe 580 585 590 His Gly Trp Pro Glu Ile Gly Ile Pro Ala Glu Gly Lys Gly Met Ile 595 600 605 Asp Leu Ile Ala Ala Val Gln Lys Gln Gln Gln Gln Thr Gly Asn His 610 615 620 Pro Ile Thr Val His Cys Ser Ala Gly Ala Gly Arg Thr Gly Thr Phe 625 630 635 640 Ile Ala Leu Ser Asn Ile Leu Glu Arg Val Lys Ala Glu Gly Leu Leu 645 650 655 Asp Val Phe Gln Ala Val Lys Ser Leu Arg Leu Gln Arg Pro His Met 660 665 670 Val Gln Thr Leu Glu Gln Tyr Glu Phe Cys Tyr Lys Val Val Gln Asp 675 680 685 Phe Ile Asp Ile Phe Ser Asp Tyr Ala Asn Phe Lys 690 695 700 <210> SEQ ID NO 64 <211> LENGTH: 2827 <212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 63, 295, 296 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 64 cacgggtccc agccctgctt taccagttgc gaaaccttaa gtgccacact actttgtggt 60 gtncagagct aaggctaaat acgaagggac gttgagtttt ctctatggct cgtctgagtg 120 ccatcacctt ttaggatcct ccctgataga gtgtcagtca gagtgcagga gagaggcatg 180 ttcctgcatc ctcccagtgt aaagccaaag ctccagaggg tgagcgccgc gtgcgctccc 240 agagccaggc accaggcgtc gccgtcgccc ctcgcagctc cacggccccg ccccnnccgc 300 ggagctggag ctggagccgg agccggagcc ctagcccaga gctggaggcg gccggaccgg 360 gccagacaga tttcctgctc tcctgtaggg ctgagggctg ccggctgcgg gctacgggct 420 gcgggctaca ggctacgggc tacggactgc gggctgcgag agaagtcacc ggcggcgcag 480 gtacctcact gcctacgcgc gtccccacga ccctccctcg cgccggcggg gacagcggac 540 gccccggagc ggagcgcgtc gggcgggcgc ccgggagatg cggagtcgcc gcggcggagc 600 gatcggggct acagcaccgg tccctgggag actatagccc tcatttcccc ttggtgcacc 660 atggagccct tctgtccact cctgctggca agttttagct tgtcgctcgc cagagctggc 720 cagggcaacg acaccacccc aacagagagc aactggacca gcacaactgc aggccctccg 780 gaccctggtg catcccagcc gctgctcacc tggctgctgc tgcccctgct cctcctcctg 840 ttcctgcttg cagcctactt cttcaggttc cggaagcaga ggaaggccgt ggtcagcagc 900 aacgacaaga aaatgcctaa cgggatctta gaagagcaag agcagcagag agtgatgctg 960 ctgagcagat ctccatcagg ccccaagaag ttcttcccca tccccgtgga gcacctggag 1020 gaggagatcc gggtgagatc tgcggatgac tgcaagcgat tccgagagga gttcaattca 1080 ttgccatctg gacacataca aggaaccttt gaactagcaa ataaagaaga aaacagagaa 1140 aaaaacagat accccaacat tctgcccaat gatcattgca gagtgatttt gagccaagtg 1200 gatggaatcc cctgctctga ctacattaat gcttcctaca tcgatggcta caaagaaaag 1260 aacaaattca tagcagctca aggccctaag caggagacag tgaatgactt ctggagaatg 1320 gtctgggagc aaaggtcagc caccatcgtc atgttgacga acctgaagga gaggaaggag 1380 gagaagtgct accagtactg gccagaccag ggctgttgga cctacggcaa catccgggtg 1440 tgtgtagagg actgcgtggt cctggtggat tacacgatcc gaaagttctg catccatccg 1500 caactcccag acagctgcaa agccccgcgg ctggtctcac agctgcactt caccagctgg 1560 cctgacttcg gggtgccgtt tacccccatc gggatgctca agttcctgaa gaaagtgaag 1620 acactcaacc cctcacatgc tgggcccatt gtggttcact gtagcgcggg cgtgggtcgg 1680 actggcacct tcattgtgat cgatgccatg atggacatga tacactcgga gcagaaggtt 1740 gacgtctttg agtttgtgtc tagaatccgc aatcagcgcc ctcagatggt ccagacggat 1800 gttcagtata cattcatcta ccaagcctta ctggaatact acctctatgg ggacacagag 1860 ctggatgtgt cctccctgga gaggcacctg cagacgctcc atagcacagc cacccatttt 1920 gacaagatcg ggctggagga agagttcagg aagctgacca acgtgcgaat catgaaggag 1980 aacatgagga cgggcaacct gcctgccaac atgaagaagg cccgcgtcat ccagatcatt 2040 ccatatgact tcaatcgggt catcctgtcc atgaaaagag ggcaagagtt cacagactat 2100 atcaacgcat ccttcataga tggctacagg cagaaggact acttcatggc cacacaggcg 2160 cctctggctc acacagttga ggacttctgg aggatggtat gggagtggaa gtctcacaca 2220 atgctcatgc tgacggaggt gcaggagcgg gaacaggata aatgctacca gtattggcca 2280 acggagggct cggtgactca tggagatata actatagaga taaagagcga caccctgtct 2340 gaagcaatca gcgtacgaga ctttctggtt accttcaaac agcccctggc ccgccaggaa 2400 gagcaggtcc gcatggtgag acaattccat ttccatggct ggcctgaggt tggcatcccc 2460 gctgaaggca aaggcatgat tgacctgatt gcagcagtgc agaagcagca gcagcagacg 2520 ggcaaccacc ccatcaccgt gcactgcagc gcgggagcag ggcggacagg tacattcata 2580 gcactcagta acattttgga acgagtgaaa gccgagggac tcctagacgt gtttcaagct 2640 gtgaagagct taagacttca gagaccacac atggtgcaga ccctggagca atatgaattc 2700 tgctacaaag tggtacaaga ttttatcgat atattttctg attatgctaa tttcaaatga 2760 agattcctgc cttaaaatat tttttaattt aatggtcagt atattttgta aaaaaaaaaa 2820 aaaaaaa 2827 <210> SEQ ID NO 65 <211> LENGTH: 699 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 65 Met Glu Pro Phe Cys Pro Leu Leu Leu Ala Ser Phe Ser Leu Ser Leu 1 5 10 15 Ala Arg Ala Gly Gln Gly Asn Asp Thr Thr Pro Thr Glu Ser Asn Trp 20 25 30 Thr Ser Thr Thr Ala Gly Pro Pro Asp Pro Gly Ala Ser Gln Pro Leu 35 40 45 Leu Thr Trp Leu Leu Leu Pro Leu Leu Leu Leu Leu Phe Leu Leu Ala 50 55 60 Ala Tyr Phe Phe Arg Phe Arg Lys Gln Arg Lys Ala Val Val Ser Ser 65 70 75 80 Asn Asp Lys Lys Met Pro Asn Gly Ile Leu Glu Glu Gln Glu Gln Gln 85 90 95 Arg Val Met Leu Leu Ser Arg Ser Pro Ser Gly Pro Lys Lys Phe Phe 100 105 110 Pro Ile Pro Val Glu His Leu Glu Glu Glu Ile Arg Val Arg Ser Ala 115 120 125 Asp Asp Cys Lys Arg Phe Arg Glu Glu Phe Asn Ser Leu Pro Ser Gly 130 135 140 His Ile Gln Gly Thr Phe Glu Leu Ala Asn Lys Glu Glu Asn Arg Glu 145 150 155 160 Lys Asn Arg Tyr Pro Asn Ile Leu Pro Asn Asp His Cys Arg Val Ile 165 170 175 Leu Ser Gln Val Asp Gly Ile Pro Cys Ser Asp Tyr Ile Asn Ala Ser 180 185 190 Tyr Ile Asp Gly Tyr Lys Glu Lys Asn Lys Phe Ile Ala Ala Gln Gly 195 200 205 Pro Lys Gln Glu Thr Val Asn Asp Phe Trp Arg Met Val Trp Glu Gln 210 215 220 Arg Ser Ala Thr Ile Val Met Leu Thr Asn Leu Lys Glu Arg Lys Glu 225 230 235 240 Glu Lys Cys Tyr Gln Tyr Trp Pro Asp Gln Gly Cys Trp Thr Tyr Gly 245 250 255 Asn Ile Arg Val Cys Val Glu Asp Cys Val Val Leu Val Asp Tyr Thr 260 265 270 Ile Arg Lys Phe Cys Ile His Pro Gln Leu Pro Asp Ser Cys Lys Ala 275 280 285 Pro Arg Leu Val Ser Gln Leu His Phe Thr Ser Trp Pro Asp Phe Gly 290 295 300 Val Pro Phe Thr Pro Ile Gly Met Leu Lys Phe Leu Lys Lys Val Lys 305 310 315 320 Thr Leu Asn Pro Ser His Ala Gly Pro Ile Val Val His Cys Ser Ala 325 330 335 Gly Val Gly Arg Thr Gly Thr Phe Ile Val Ile Asp Ala Met Met Asp 340 345 350 Met Ile His Ser Glu Gln Lys Val Asp Val Phe Glu Phe Val Ser Arg 355 360 365 Ile Arg Asn Gln Arg Pro Gln Met Val Gln Thr Asp Val Gln Tyr Thr 370 375 380 Phe Ile Tyr Gln Ala Leu Leu Glu Tyr Tyr Leu Tyr Gly Asp Thr Glu 385 390 395 400 Leu Asp Val Ser Ser Leu Glu Arg His Leu Gln Thr Leu His Ser Thr 405 410 415 Ala Thr His Phe Asp Lys Ile Gly Leu Glu Glu Glu Phe Arg Lys Leu 420 425 430 Thr Asn Val Arg Ile Met Lys Glu Asn Met Arg Thr Gly Asn Leu Pro 435 440 445 Ala Asn Met Lys Lys Ala Arg Val Ile Gln Ile Ile Pro Tyr Asp Phe 450 455 460 Asn Arg Val Ile Leu Ser Met Lys Arg Gly Gln Glu Phe Thr Asp Tyr 465 470 475 480 Ile Asn Ala Ser Phe Ile Asp Gly Tyr Arg Gln Lys Asp Tyr Phe Met 485 490 495 Ala Thr Gln Ala Pro Leu Ala His Thr Val Glu Asp Phe Trp Arg Met 500 505 510 Val Trp Glu Trp Lys Ser His Thr Met Leu Met Leu Thr Glu Val Gln 515 520 525 Glu Arg Glu Gln Asp Lys Cys Tyr Gln Tyr Trp Pro Thr Glu Gly Ser 530 535 540 Val Thr His Gly Asp Ile Thr Ile Glu Ile Lys Ser Asp Thr Leu Ser 545 550 555 560 Glu Ala Ile Ser Val Arg Asp Phe Leu Val Thr Phe Lys Gln Pro Leu 565 570 575 Ala Arg Gln Glu Glu Gln Val Arg Met Val Arg Gln Phe His Phe His 580 585 590 Gly Trp Pro Glu Val Gly Ile Pro Ala Glu Gly Lys Gly Met Ile Asp 595 600 605 Leu Ile Ala Ala Val Gln Lys Gln Gln Gln Gln Thr Gly Asn His Pro 610 615 620 Ile Thr Val His Cys Ser Ala Gly Ala Gly Arg Thr Gly Thr Phe Ile 625 630 635 640 Ala Leu Ser Asn Ile Leu Glu Arg Val Lys Ala Glu Gly Leu Leu Asp 645 650 655 Val Phe Gln Ala Val Lys Ser Leu Arg Leu Gln Arg Pro His Met Val 660 665 670 Gln Thr Leu Glu Gln Tyr Glu Phe Cys Tyr Lys Val Val Gln Asp Phe 675 680 685 Ile Asp Ile Phe Ser Asp Tyr Ala Asn Phe Lys 690 695 <210> SEQ ID NO 66 <211> LENGTH: 2155 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 66 cccaaacagt tcagataccg ctggtcaggc ctgcgctgta cacagctcag ccatgagcag 60 cagaaagaac ttttccaggc tcacctggtt caggaagcag aggaaagccg tggtcaacag 120 caacgacaag aagatgccta acgggatcct agaagaacaa gagcagcaga gagtgatgct 180 actgagcaga tctccatcgg gtcccaagaa gtacttcccc atccctgtgg agcacctgga 240 ggaggagatc cgggtgagat ctgcggatga ctgcaagcgg ttccgagagg agttcaattc 300 attgccatcc ggacacatac aaggaacctt tgaactagca aataaagaag aaaacagaga 360 aaaaaacaga taccccaaca ttctgcccaa tgatcattgc agagtgattt tgagccaatt 420 ggatggaatc ccctgctctg actacattaa tgcttcctac atagatggct acaaagaaaa 480 gaacaaattc atagcagctc aaggccccaa gcaggagaca gtgaatgact tctggagaat 540 ggtctgggag caaaggtcag ccaccattgt catgttgacg aacctgaagg aaaggaagga 600 ggagaagtgc taccagtact ggccagacca gggctgttgg acttatggga acatccgggt 660 gtgtgtagag gactgcgtgg tcctggtgga ttacaccatc cgcaagttct gcatccatcc 720 gcaactcccc gacagctgca aagctccacg gctggtctca cagctgcact tcaccagctg 780 gcctgacttt ggggtaccat ttacccccat cggaatgctg aagttcctga agaaagtgaa 840 gacactcaac ccctcacatg ctgggcccat tgtggtccac tgtagcgcgg gcgtgggtcg 900 gactggcacc ttcattgtga tcgatgccat gatggacatg atccactcgg aacagaaggt 960 tgacgtcttc gagtttgtgt ctagaatccg caatcagcgc cctcagatgg tccagacaga 1020 tgttcagtat acattcatct accaagcctt actggaatac tacctctatg gggacacgga 1080 gctggatgtg tcctccttgg agaggcacct gcagacgcta catggcacag ccacccattt 1140 tgacaagatc gggctggagg aagaattcag gaaactgacc aacgtgcgaa tcatgaagga 1200 gaacatgagg acgggcaacc tgccggccaa catgaagaag gcccgtgtaa tccagatcat 1260 cccatatgac ttcaatcggg taatcctgtc catgaaaaga gggcaagagt tcacagacta 1320 catcaatgca tccttcatag atggctacag gcagaaggac tacttcatgg ctacacaggg 1380 gcctctggcg cacacagttg aggacttctg gaggatggtc tgggagtgga agtcacacac 1440 aatcgtcatg ctgactgagg tgcaggagcg ggagcaggat aaatgctacc agtattggcc 1500 aaccgagggc tcagtgactc acggagatat aactatagaa ataaagagtg acaccctgtc 1560 tgaagcaatc agcatacgag actttctggt tactttcaca cagcccctgg cccgccagga 1620 agagcaggtc cggatggtga gacaattcca tttccatgcc tggcctgagg ttggaatccc 1680 cactgagggt aaaggcatga ttgacctgct ctcggcagtg cagaagcagc agcagcagac 1740 agacaaccac cccatcaccg tgcactgcag tgcgggagca gggcggacag gtacattcat 1800 agcactcagt aacattttgg aacgagtgaa agccgaggga ctcctagatg tgtttcaagc 1860 tgtgaagagc ttaagacttc agagaccaca catggtgcaa accctggagc aatatgaatt 1920 ctgctacaaa gtggtacaag attttatcga tatattttct gattatgcta atttcaaatg 1980 aagatccctg ccttaaaata ttttttaatt taatggtcag tatattttgt aaaaaaaatc 2040 atgttaattt atttcctagt ggatattaat atccgtcctg attcctttgg tatatatttt 2100 gttatgttct aaaggctacc tgctgtaaga ttattaaatc ataaatgtcc ttttt 2155 <210> SEQ ID NO 67 <211> LENGTH: 659 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 67 Pro Asn Ser Ser Asp Thr Ala Gly Gln Ala Cys Ala Val His Ser Ser 1 5 10 15 Ala Met Ser Ser Arg Lys Asn Phe Ser Arg Leu Thr Trp Phe Arg Lys 20 25 30 Gln Arg Lys Ala Val Val Asn Ser Asn Asp Lys Lys Met Pro Asn Gly 35 40 45 Ile Leu Glu Glu Gln Glu Gln Gln Arg Val Met Leu Leu Ser Arg Ser 50 55 60 Pro Ser Gly Pro Lys Lys Tyr Phe Pro Ile Pro Val Glu His Leu Glu 65 70 75 80 Glu Glu Ile Arg Val Arg Ser Ala Asp Asp Cys Lys Arg Phe Arg Glu 85 90 95 Glu Phe Asn Ser Leu Pro Ser Gly His Ile Gln Gly Thr Phe Glu Leu 100 105 110 Ala Asn Lys Glu Glu Asn Arg Glu Lys Asn Arg Tyr Pro Asn Ile Leu 115 120 125 Pro Asn Asp His Cys Arg Val Ile Leu Ser Gln Leu Asp Gly Ile Pro 130 135 140 Cys Ser Asp Tyr Ile Asn Ala Ser Tyr Ile Asp Gly Tyr Lys Glu Lys 145 150 155 160 Asn Lys Phe Ile Ala Ala Gln Gly Pro Lys Gln Glu Thr Val Asn Asp 165 170 175 Phe Trp Arg Met Val Trp Glu Gln Arg Ser Ala Thr Ile Val Met Leu 180 185 190 Thr Asn Leu Lys Glu Arg Lys Glu Glu Lys Cys Tyr Gln Tyr Trp Pro 195 200 205 Asp Gln Gly Cys Trp Thr Tyr Gly Asn Ile Arg Val Cys Val Glu Asp 210 215 220 Cys Val Val Leu Val Asp Tyr Thr Ile Arg Lys Phe Cys Ile His Pro 225 230 235 240 Gln Leu Pro Asp Ser Cys Lys Ala Pro Arg Leu Val Ser Gln Leu His 245 250 255 Phe Thr Ser Trp Pro Asp Phe Gly Val Pro Phe Thr Pro Ile Gly Met 260 265 270 Leu Lys Phe Leu Lys Lys Val Lys Thr Leu Asn Pro Ser His Ala Gly 275 280 285 Pro Ile Val Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr Phe 290 295 300 Ile Val Ile Asp Ala Met Met Asp Met Ile His Ser Glu Gln Lys Val 305 310 315 320 Asp Val Phe Glu Phe Val Ser Arg Ile Arg Asn Gln Arg Pro Gln Met 325 330 335 Val Gln Thr Asp Val Gln Tyr Thr Phe Ile Tyr Gln Ala Leu Leu Glu 340 345 350 Tyr Tyr Leu Tyr Gly Asp Thr Glu Leu Asp Val Ser Ser Leu Glu Arg 355 360 365 His Leu Gln Thr Leu His Gly Thr Ala Thr His Phe Asp Lys Ile Gly 370 375 380 Leu Glu Glu Glu Phe Arg Lys Leu Thr Asn Val Arg Ile Met Lys Glu 385 390 395 400 Asn Met Arg Thr Gly Asn Leu Pro Ala Asn Met Lys Lys Ala Arg Val 405 410 415 Ile Gln Ile Ile Pro Tyr Asp Phe Asn Arg Val Ile Leu Ser Met Lys 420 425 430 Arg Gly Gln Glu Phe Thr Asp Tyr Ile Asn Ala Ser Phe Ile Asp Gly 435 440 445 Tyr Arg Gln Lys Asp Tyr Phe Met Ala Thr Gln Gly Pro Leu Ala His 450 455 460 Thr Val Glu Asp Phe Trp Arg Met Val Trp Glu Trp Lys Ser His Thr 465 470 475 480 Ile Val Met Leu Thr Glu Val Gln Glu Arg Glu Gln Asp Lys Cys Tyr 485 490 495 Gln Tyr Trp Pro Thr Glu Gly Ser Val Thr His Gly Asp Ile Thr Ile 500 505 510 Glu Ile Lys Ser Asp Thr Leu Ser Glu Ala Ile Ser Ile Arg Asp Phe 515 520 525 Leu Val Thr Phe Thr Gln Pro Leu Ala Arg Gln Glu Glu Gln Val Arg 530 535 540 Met Val Arg Gln Phe His Phe His Ala Trp Pro Glu Val Gly Ile Pro 545 550 555 560 Thr Glu Gly Lys Gly Met Ile Asp Leu Leu Ser Ala Val Gln Lys Gln 565 570 575 Gln Gln Gln Thr Asp Asn His Pro Ile Thr Val His Cys Ser Ala Gly 580 585 590 Ala Gly Arg Thr Gly Thr Phe Ile Ala Leu Ser Asn Ile Leu Glu Arg 595 600 605 Val Lys Ala Glu Gly Leu Leu Asp Val Phe Gln Ala Val Lys Ser Leu 610 615 620 Arg Leu Gln Arg Pro His Met Val Gln Thr Leu Glu Gln Tyr Glu Phe 625 630 635 640 Cys Tyr Lys Val Val Gln Asp Phe Ile Asp Ile Phe Ser Asp Tyr Ala 645 650 655 Asn Phe Lys <210> SEQ ID NO 68 <211> LENGTH: 2938 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 gccgggggga cgcgggagga tggagcaagt ggagatcctg aggaaattca tccagagggt 60 ccaggccatg aagagtcctg accacaatgg ggaggacaac ttcgcccggg acttcatgcg 120 gttaagaaga ttgtctacca aatatagaac agaaaagata tatcccacag ccactggaga 180 aaaagaagaa aatgttaaaa agaacagata caaggacata ctgccatttg atcacagccg 240 agttaaattg acattaaaga ctccttcaca agattcagac tatatcaatg caaattttat 300 aaagggcgtc tatgggccaa aagcatatgt agcaactcaa ggacctttag caaatacagt 360 aatagatttt tggaggatgg tatgggagta taatgttgtg atcattgtaa tggcctgccg 420 agaatttgag atgggaagga aaaaatgtga gcgctattgg cctttgtatg gagaagaccc 480 cataacgttt gcaccattta aaatttcttg tgaggatgaa caagcaagaa cagactactt 540 catcaggaca ctcttacttg aatttcaaaa tgaatctcgt aggctgtatc agtttcatta 600 tgtgaactgg ccagaccatg atgttccttc atcatttgat tctattctgg acatgataag 660 cttaatgagg aaatatcaag aacatgaaga tgttcctatt tgtattcatt gcagtgcagg 720 ctgtggaaga acaggtgcca tttgtgccat agattatacg tggaatttac taaaagctgg 780 gaaaatacca gaggaattta atgtatttaa tttaatacaa gaaatgagaa cacaaaggca 840 ttctgcagta caaacaaagg agcaatatga acttgttcat agagctattg cccaactgtt 900 tgaaaaacag ctacaactat atgaaattca tggagctcag aaaattgctg atggagtgaa 960 tgaaattaac actgaaaaca tggtcagctc catagagcct gaaaaacaag attctcctcc 1020 tccaaaacca ccaaggaccc gcagttgcct tgttgaaggg gatgctaaag aagaaatact 1080 gcagccaccg gaacctcatc cagtgccacc catcttgaca ccttctcccc cttcagcttt 1140 tccaacagtc actactgtgt ggcaggacaa tgatagatac catccaaagc cagtgttgca 1200 tatggtttca tcagaacaac attcagcaga cctcaacaga aactatagta aatcaacaga 1260 acttccaggg aaaaatgaat caacaattga acagatagat aaaaaattgg aacgaaattt 1320 aagttttgag attaagaagg tccctctcca agagggacca aaaagttttg atgggaacac 1380 acttttgaat aggggacatg caattaaaat taaatctgct tcaccttgta tagctgataa 1440 aatctctaag ccacaggaat taagttcaga tctaaatgtc ggtgatactt cccagaattc 1500 ttgtgtggac tgcagtgtaa cacaatcaaa caaagtttca gttactccac cagaagaatc 1560 ccagaattca gacacacctc caaggccaga ccgcttgcct cttgatgaga aaggacatgt 1620 aacgtggtca tttcatggac ctgaaaatgc catacccata cctgatttat ctgaaggcaa 1680 ttcctcagat atcaactatc aaactaggaa aactgtgagt ttaacaccaa gtcctacaac 1740 acaagttgaa acacctgatc ttgtggatca tgataacact tcaccactct tcagaacacc 1800 cctcagtttt actaatccac ttcactctga tgactcagac tcagatgaaa gaaactctga 1860 tggtgctgtg acccagaata aaactaatat ttcaacagca agtgccacag tttctgctgc 1920 cactagtact gaaagcattt ctactaggaa agtattgcca atgtccattg ctagacataa 1980 tatagcagga acaacacatt caggtgctga aaaagatgtt gatgttagtg aagattcacc 2040 tcctccccta cctgaaagaa ctcctgaatc gtttgtgtta gcaagtgaac ataatacacc 2100 tgtaagatcg gaatggagtg aacttcaaag tcaggaacga tctgaacaaa aaaagtctga 2160 aggcttgata acctctgaaa atgagaaatg tgatcatcca gcgggaggta ttcactatga 2220 aatgtgcata gaatgtccac ctactttcag tgacaagaga gaacaaatat cagaaaatcc 2280 aacagaagcc acagatattg gttttggtaa tcgatgtgga aaacccaaag gaccaagaga 2340 tccaccttca gaatggacat gattcaggga gctagaagac actttaagtt atactggaaa 2400 attcaggtgc cactgaaagc cagatttata gtattccatc tttaatatgt gggactaaca 2460 gcagtgtaga ttgttacctt aatatttttt gctgggacca tctacctgcc ttatactaca 2520 cttaggaaaa agtattacat atggtttatt ttgaaacttc aagtattatt gccttaatgt 2580 ctcttaaccc tgttacacgc tgcttgtaga catgttaata tagtaatacc tttatgatat 2640 attgagttta aggactaccc tttttctgtt ttatcatgta ttcattattt tgtatatgta 2700 cagggcaagt aggtatataa tttgataaag ttgcaattga aatattatta acagaagatg 2760 taagaaattt ctgcatggtc taaatctttg tgtactttat ttgtaaatta tttgccctgg 2820 agttttagaa aatagtttct gaattttaaa cttgctggat tcatgcagcc agctttgcag 2880 gttatcagag atcaaagatt gtaataataa ttttgtaaat tgtaagcaaa cattctgc 2938 <210> SEQ ID NO 69 <211> LENGTH: 780 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 69 Met Glu Gln Val Glu Ile Leu Arg Lys Phe Ile Gln Arg Val Gln Ala 1 5 10 15 Met Lys Ser Pro Asp His Asn Gly Glu Asp Asn Phe Ala Arg Asp Phe 20 25 30 Met Arg Leu Arg Arg Leu Ser Thr Lys Tyr Arg Thr Glu Lys Ile Tyr 35 40 45 Pro Thr Ala Thr Gly Glu Lys Glu Glu Asn Val Lys Lys Asn Arg Tyr 50 55 60 Lys Asp Ile Leu Pro Phe Asp His Ser Arg Val Lys Leu Thr Leu Lys 65 70 75 80 Thr Pro Ser Gln Asp Ser Asp Tyr Ile Asn Ala Asn Phe Ile Lys Gly 85 90 95 Val Tyr Gly Pro Lys Ala Tyr Val Ala Thr Gln Gly Pro Leu Ala Asn 100 105 110 Thr Val Ile Asp Phe Trp Arg Met Val Trp Glu Tyr Asn Val Val Ile 115 120 125 Ile Val Met Ala Cys Arg Glu Phe Glu Met Gly Arg Lys Lys Cys Glu 130 135 140 Arg Tyr Trp Pro Leu Tyr Gly Glu Asp Pro Ile Thr Phe Ala Pro Phe 145 150 155 160 Lys Ile Ser Cys Glu Asp Glu Gln Ala Arg Thr Asp Tyr Phe Ile Arg 165 170 175 Thr Leu Leu Leu Glu Phe Gln Asn Glu Ser Arg Arg Leu Tyr Gln Phe 180 185 190 His Tyr Val Asn Trp Pro Asp His Asp Val Pro Ser Ser Phe Asp Ser 195 200 205 Ile Leu Asp Met Ile Ser Leu Met Arg Lys Tyr Gln Glu His Glu Asp 210 215 220 Val Pro Ile Cys Ile His Cys Ser Ala Gly Cys Gly Arg Thr Gly Ala 225 230 235 240 Ile Cys Ala Ile Asp Tyr Thr Trp Asn Leu Leu Lys Ala Gly Lys Ile 245 250 255 Pro Glu Glu Phe Asn Val Phe Asn Leu Ile Gln Glu Met Arg Thr Gln 260 265 270 Arg His Ser Ala Val Gln Thr Lys Glu Gln Tyr Glu Leu Val His Arg 275 280 285 Ala Ile Ala Gln Leu Phe Glu Lys Gln Leu Gln Leu Tyr Glu Ile His 290 295 300 Gly Ala Gln Lys Ile Ala Asp Gly Val Asn Glu Ile Asn Thr Glu Asn 305 310 315 320 Met Val Ser Ser Ile Glu Pro Glu Lys Gln Asp Ser Pro Pro Pro Lys 325 330 335 Pro Pro Arg Thr Arg Ser Cys Leu Val Glu Gly Asp Ala Lys Glu Glu 340 345 350 Ile Leu Gln Pro Pro Glu Pro His Pro Val Pro Pro Ile Leu Thr Pro 355 360 365 Ser Pro Pro Ser Ala Phe Pro Thr Val Thr Thr Val Trp Gln Asp Asn 370 375 380 Asp Arg Tyr His Pro Lys Pro Val Leu His Met Val Ser Ser Glu Gln 385 390 395 400 His Ser Ala Asp Leu Asn Arg Asn Tyr Ser Lys Ser Thr Glu Leu Pro 405 410 415 Gly Lys Asn Glu Ser Thr Ile Glu Gln Ile Asp Lys Lys Leu Glu Arg 420 425 430 Asn Leu Ser Phe Glu Ile Lys Lys Val Pro Leu Gln Glu Gly Pro Lys 435 440 445 Ser Phe Asp Gly Asn Thr Leu Leu Asn Arg Gly His Ala Ile Lys Ile 450 455 460 Lys Ser Ala Ser Pro Cys Ile Ala Asp Lys Ile Ser Lys Pro Gln Glu 465 470 475 480 Leu Ser Ser Asp Leu Asn Val Gly Asp Thr Ser Gln Asn Ser Cys Val 485 490 495 Asp Cys Ser Val Thr Gln Ser Asn Lys Val Ser Val Thr Pro Pro Glu 500 505 510 Glu Ser Gln Asn Ser Asp Thr Pro Pro Arg Pro Asp Arg Leu Pro Leu 515 520 525 Asp Glu Lys Gly His Val Thr Trp Ser Phe His Gly Pro Glu Asn Ala 530 535 540 Ile Pro Ile Pro Asp Leu Ser Glu Gly Asn Ser Ser Asp Ile Asn Tyr 545 550 555 560 Gln Thr Arg Lys Thr Val Ser Leu Thr Pro Ser Pro Thr Thr Gln Val 565 570 575 Glu Thr Pro Asp Leu Val Asp His Asp Asn Thr Ser Pro Leu Phe Arg 580 585 590 Thr Pro Leu Ser Phe Thr Asn Pro Leu His Ser Asp Asp Ser Asp Ser 595 600 605 Asp Glu Arg Asn Ser Asp Gly Ala Val Thr Gln Asn Lys Thr Asn Ile 610 615 620 Ser Thr Ala Ser Ala Thr Val Ser Ala Ala Thr Ser Thr Glu Ser Ile 625 630 635 640 Ser Thr Arg Lys Val Leu Pro Met Ser Ile Ala Arg His Asn Ile Ala 645 650 655 Gly Thr Thr His Ser Gly Ala Glu Lys Asp Val Asp Val Ser Glu Asp 660 665 670 Ser Pro Pro Pro Leu Pro Glu Arg Thr Pro Glu Ser Phe Val Leu Ala 675 680 685 Ser Glu His Asn Thr Pro Val Arg Ser Glu Trp Ser Glu Leu Gln Ser 690 695 700 Gln Glu Arg Ser Glu Gln Lys Lys Ser Glu Gly Leu Ile Thr Ser Glu 705 710 715 720 Asn Glu Lys Cys Asp His Pro Ala Gly Gly Ile His Tyr Glu Met Cys 725 730 735 Ile Glu Cys Pro Pro Thr Phe Ser Asp Lys Arg Glu Gln Ile Ser Glu 740 745 750 Asn Pro Thr Glu Ala Thr Asp Ile Gly Phe Gly Asn Arg Cys Gly Lys 755 760 765 Pro Lys Gly Pro Arg Asp Pro Pro Ser Glu Trp Thr 770 775 780 <210> SEQ ID NO 70 <211> LENGTH: 3160 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 70 agcgaccgca gccgggggga cgcgggagga tggagcaagt ggagatcctg aggaaattca 60 tccagagggt ccaggccatg aagagtcctg accacaatgg ggaggacaac ttcgcccggg 120 acttcatgcg gttaagaaga ttgtctacca aatatagaac agaaaagata tatcccacag 180 ccactggaga aaaagaagaa aatgttaaaa agaacagata caaggacata ctgccatttg 240 atcacagccg agttaaattg acattaaaga ctccttcaca agattcagac tatatcaatg 300 caaattttat aaagggcgtc tatgggccaa aagcatatgt agcaactcaa ggacctttag 360 caaatacagt aatagatttt tggaggatga tatgggagta taatgttgtg atcattgtaa 420 tggcctgccg agaatttgag atgggaagga aaaaatgtga gcgctattgg cctttgtatg 480 gagaagaccc cataacgttt gcaccattta aaatttcttg tgaggatgaa caagcaagaa 540 cagactactt catcaggaca ctcttacttg aatttcaaaa tgaatctcgt aggctgtatc 600 agtttcatta tgtgaactgg ccagaccatg atgttccttc atcatttgat tctattctgg 660 acatgataag cttaatgagg aaatatcaag aacatgaaga tgttcctatt tgtattcatt 720 gcagtgcagg ctgtggaaga acaggtgcca tttgtgccat agattatacg tggaatttac 780 taaaagctgg gaaaatacca gaggaattta atgtatttaa tttaatacaa gaaatgagaa 840 cacaaaggca ttctgcagta caaacaaagg agcaatatga acttgttcat agagctattg 900 cccaactgtt tgaaaaacag ctacaactat atgaaattca tggagctcag aaaattgctg 960 atggagtgaa tgaaattaac actgaaaaca tgatcagctc catagagcct gaaaaacaag 1020 attctcctcc tccaaaacca ccaaggaccc gcagttgcct tgttgaaggg gatgctaaag 1080 aagaaatact gcagccaccg gaacctcatc cagtgccacc catcttgaca ccttctcccc 1140 cttcagcttt tccaacagtc actactgtgt ggcaggacaa tgatagatac catccaaagc 1200 cagtgttgca tatggtttca tcagaacaac attcagcaga cctcaacaga aactatagta 1260 aatcaacaga acttccaggg aaaaatgaat caacaattga acagatagat aaaaaattgg 1320 aacgaaattt aagttttgag attaagaagg tccctctcca agagggacca aaaagttttg 1380 atgggaacac acttttgaat aggggacatg caattaaaat taaatctgct tcaccttgta 1440 tagctgataa aatctctaag ccacaggaat taagttcaga tctaaatgtc ggtgatactt 1500 cccagaattc ttgtgtggac tgcagtgtaa cacaatcaaa caaagtttca gttactccac 1560 cagaagaatc ccagaattca gacacacctc caaggccaga ccgcttgcct cttgatgaga 1620 aaggacatgt aacgtggtca tttcatggac ctgaaaatgc catacccata cctgatttat 1680 ctgaaggcaa ttcctcagat atcaactatc aaactaggaa aactgtgagt ttaacaccaa 1740 gtcctacaac acaagttgaa acacctgatc ttgtggatca tgataacact tcaccactct 1800 tcagaacacc cctcagtttt actaatccac ttcactctga tgactcagac tcagatgaaa 1860 gaaactctga tggtgctgtg acccagaata aaactaatat ttcaacagca agtgccacag 1920 tttctgctgc cactagtact gaaagcattt ctactaggaa agtattgcca atgtccattg 1980 ctagacataa tatagcagga acaacacatt caggtgctga aaaagatgtt gatgttagtg 2040 aagattcacc tcctccccta cctgaaagaa ctcctgaatc gtttgtgtta gcaagtgaac 2100 ataatacacc tgtaagatcg gaatggagtg aacttcaaag tcaggaacga tctgaacaaa 2160 aaaagtctga aggcttgata acctctgaaa atgagaaatg tgatcatcca gcgggaggta 2220 ttcactatga aatgtgcata gaatgtccac ctactttcag tgacaagaga gaacaaatat 2280 cagaaaatcc aacagaagcc acagatattg gttttggtaa tcgatgtgga aaacccaaag 2340 gaccaagaga tccaccttca gaatggacat gattcaggga gctagaagac actttaagtt 2400 atactggaaa attcaggtgc cactgaaagc cagatttata gtattccatc tttaatatgt 2460 gggactaaca gcagtgtaga ttgttacctt aatatttttt gctgggacca tctacctgcc 2520 ttatactaca cttaggaaaa agtattacat atggtttatt ttgaaacttc aagtattatt 2580 gccttaatgt ctcttaaccc tgttacacgc tgcttgtaga catgttaata tagtaatacc 2640 tttatgatat attgagttta aggactactc tttttctgtt ttatcatgta tgcattattt 2700 tgtatatgta cagggcaagt aggtatataa tttgataaag ttgcaattga aatattatta 2760 acagaagatg taagaaattt ctgcatggtc taaatctttg tgtactttat ttgtaaatta 2820 tttgccctgg agttttagaa aatagtttct gaattttaaa cttgctggat tcatgcagcc 2880 agctttgcag gttatcagag atcaaagatt gtaataataa ttttgtaaat tgtaagcaaa 2940 aagttatttt tatattatat acagtctaat tgttcatcct aattgttcct gttttcatct 3000 agtcagagat tcagtaagtg ccttggaaca atattgaatt ctcttagctt gtgtgtgttt 3060 ctttaatatt tgaactcaag tgggattaga agactatcaa aatacatgta tgtttcagat 3120 atttgacctg tcattaaaaa aaacaaacag ttttacagtg 3160 <210> SEQ ID NO 71 <211> LENGTH: 780 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 71 Met Glu Gln Val Glu Ile Leu Arg Lys Phe Ile Gln Arg Val Gln Ala 1 5 10 15 Met Lys Ser Pro Asp His Asn Gly Glu Asp Asn Phe Ala Arg Asp Phe 20 25 30 Met Arg Leu Arg Arg Leu Ser Thr Lys Tyr Arg Thr Glu Lys Ile Tyr 35 40 45 Pro Thr Ala Thr Gly Glu Lys Glu Glu Asn Val Lys Lys Asn Arg Tyr 50 55 60 Lys Asp Ile Leu Pro Phe Asp His Ser Arg Val Lys Leu Thr Leu Lys 65 70 75 80 Thr Pro Ser Gln Asp Ser Asp Tyr Ile Asn Ala Asn Phe Ile Lys Gly 85 90 95 Val Tyr Gly Pro Lys Ala Tyr Val Ala Thr Gln Gly Pro Leu Ala Asn 100 105 110 Thr Val Ile Asp Phe Trp Arg Met Ile Trp Glu Tyr Asn Val Val Ile 115 120 125 Ile Val Met Ala Cys Arg Glu Phe Glu Met Gly Arg Lys Lys Cys Glu 130 135 140 Arg Tyr Trp Pro Leu Tyr Gly Glu Asp Pro Ile Thr Phe Ala Pro Phe 145 150 155 160 Lys Ile Ser Cys Glu Asp Glu Gln Ala Arg Thr Asp Tyr Phe Ile Arg 165 170 175 Thr Leu Leu Leu Glu Phe Gln Asn Glu Ser Arg Arg Leu Tyr Gln Phe 180 185 190 His Tyr Val Asn Trp Pro Asp His Asp Val Pro Ser Ser Phe Asp Ser 195 200 205 Ile Leu Asp Met Ile Ser Leu Met Arg Lys Tyr Gln Glu His Glu Asp 210 215 220 Val Pro Ile Cys Ile His Cys Ser Ala Gly Cys Gly Arg Thr Gly Ala 225 230 235 240 Ile Cys Ala Ile Asp Tyr Thr Trp Asn Leu Leu Lys Ala Gly Lys Ile 245 250 255 Pro Glu Glu Phe Asn Val Phe Asn Leu Ile Gln Glu Met Arg Thr Gln 260 265 270 Arg His Ser Ala Val Gln Thr Lys Glu Gln Tyr Glu Leu Val His Arg 275 280 285 Ala Ile Ala Gln Leu Phe Glu Lys Gln Leu Gln Leu Tyr Glu Ile His 290 295 300 Gly Ala Gln Lys Ile Ala Asp Gly Val Asn Glu Ile Asn Thr Glu Asn 305 310 315 320 Met Ile Ser Ser Ile Glu Pro Glu Lys Gln Asp Ser Pro Pro Pro Lys 325 330 335 Pro Pro Arg Thr Arg Ser Cys Leu Val Glu Gly Asp Ala Lys Glu Glu 340 345 350 Ile Leu Gln Pro Pro Glu Pro His Pro Val Pro Pro Ile Leu Thr Pro 355 360 365 Ser Pro Pro Ser Ala Phe Pro Thr Val Thr Thr Val Trp Gln Asp Asn 370 375 380 Asp Arg Tyr His Pro Lys Pro Val Leu His Met Val Ser Ser Glu Gln 385 390 395 400 His Ser Ala Asp Leu Asn Arg Asn Tyr Ser Lys Ser Thr Glu Leu Pro 405 410 415 Gly Lys Asn Glu Ser Thr Ile Glu Gln Ile Asp Lys Lys Leu Glu Arg 420 425 430 Asn Leu Ser Phe Glu Ile Lys Lys Val Pro Leu Gln Glu Gly Pro Lys 435 440 445 Ser Phe Asp Gly Asn Thr Leu Leu Asn Arg Gly His Ala Ile Lys Ile 450 455 460 Lys Ser Ala Ser Pro Cys Ile Ala Asp Lys Ile Ser Lys Pro Gln Glu 465 470 475 480 Leu Ser Ser Asp Leu Asn Val Gly Asp Thr Ser Gln Asn Ser Cys Val 485 490 495 Asp Cys Ser Val Thr Gln Ser Asn Lys Val Ser Val Thr Pro Pro Glu 500 505 510 Glu Ser Gln Asn Ser Asp Thr Pro Pro Arg Pro Asp Arg Leu Pro Leu 515 520 525 Asp Glu Lys Gly His Val Thr Trp Ser Phe His Gly Pro Glu Asn Ala 530 535 540 Ile Pro Ile Pro Asp Leu Ser Glu Gly Asn Ser Ser Asp Ile Asn Tyr 545 550 555 560 Gln Thr Arg Lys Thr Val Ser Leu Thr Pro Ser Pro Thr Thr Gln Val 565 570 575 Glu Thr Pro Asp Leu Val Asp His Asp Asn Thr Ser Pro Leu Phe Arg 580 585 590 Thr Pro Leu Ser Phe Thr Asn Pro Leu His Ser Asp Asp Ser Asp Ser 595 600 605 Asp Glu Arg Asn Ser Asp Gly Ala Val Thr Gln Asn Lys Thr Asn Ile 610 615 620 Ser Thr Ala Ser Ala Thr Val Ser Ala Ala Thr Ser Thr Glu Ser Ile 625 630 635 640 Ser Thr Arg Lys Val Leu Pro Met Ser Ile Ala Arg His Asn Ile Ala 645 650 655 Gly Thr Thr His Ser Gly Ala Glu Lys Asp Val Asp Val Ser Glu Asp 660 665 670 Ser Pro Pro Pro Leu Pro Glu Arg Thr Pro Glu Ser Phe Val Leu Ala 675 680 685 Ser Glu His Asn Thr Pro Val Arg Ser Glu Trp Ser Glu Leu Gln Ser 690 695 700 Gln Glu Arg Ser Glu Gln Lys Lys Ser Glu Gly Leu Ile Thr Ser Glu 705 710 715 720 Asn Glu Lys Cys Asp His Pro Ala Gly Gly Ile His Tyr Glu Met Cys 725 730 735 Ile Glu Cys Pro Pro Thr Phe Ser Asp Lys Arg Glu Gln Ile Ser Glu 740 745 750 Asn Pro Thr Glu Ala Thr Asp Ile Gly Phe Gly Asn Arg Cys Gly Lys 755 760 765 Pro Lys Gly Pro Arg Asp Pro Pro Ser Glu Trp Thr 770 775 780 <210> SEQ ID NO 72 <211> LENGTH: 236 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 gttaaaagga acagatacaa ggacatactg ccatttgatc acagccgagt taaattgaca 60 ttaaagactc cttcacaaga ttcagactat atcaatgcaa attttataaa gggcgtctat 120 gggccaaaag catatgtagc aactcaagga cctttagcaa atacagtaat agatttttgg 180 aggatggtat gggagtataa tgttgtgatc attgtaatgg cctgccgaga atttga 236 <210> SEQ ID NO 73 <211> LENGTH: 78 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 73 Val Lys Arg Asn Arg Tyr Lys Asp Ile Leu Pro Phe Asp His Ser Arg 1 5 10 15 Val Lys Leu Thr Leu Lys Thr Pro Ser Gln Asp Ser Asp Tyr Ile Asn 20 25 30 Ala Asn Phe Ile Lys Gly Val Tyr Gly Pro Lys Ala Tyr Val Ala Thr 35 40 45 Gln Gly Pro Leu Ala Asn Thr Val Ile Asp Phe Trp Arg Met Val Trp 50 55 60 Glu Tyr Asn Val Val Ile Ile Val Met Ala Cys Arg Glu Phe 65 70 75 <210> SEQ ID NO 74 <211> LENGTH: 2676 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 74 gaattcgcgg ccgctgtcca gctctggcgg cggcggcttc ttctcagtag tgtaggtctc 60 tgggggcggc acgagttgga cttccagatc ttgaactcct ttggaggctc ctccggcgct 120 ttcaccacat gccgctccca gtcgatctgc ttgttcgcct cgtagtaggg gaaagcgacg 180 ctgctcttta agttgcgcgg ggagcccggc cggtgccgcc gcagccgcag ccgcctgcgc 240 ggcggggagg gagggcgggc cggagcgagc tggggaagac ggagcgggcg ctgcggcgcg 300 cgggcgggcg gcggggggga cgcgggagga tggagcaagt ggagatcctg aggaggttca 360 tccagagggt ccaggccatg aagagtccgg atcacaatgg ggaggacaac ttcgcccggg 420 acttcatgcg attgagaaga ttgtctacca aatatagaac agaaaagatt tatcccacag 480 ccactggaga aaaagaagaa aatgttaaaa agaacagata taaggacata ctgccatttg 540 atcacagccg agttaagttg actttgaaga ctccatccca agattcagat tatatcaatg 600 caaattttat taagggtgtg tatgggccaa aagcatatgt ggcaacccaa gggcctttcc 660 ggaatacagt catagacttc tggaggatga tatgggagta taatgttgtg atgatcgtga 720 tggcctgtcg agaatttgag atgggaagga aaaagtgtga gcgctactgg cctttgtatg 780 gagaagatcc tataacattt gcaccattta aaatttcttg tgaaaatgaa caagcaagaa 840 ccgactactt catccgaaca cttttacttg aatttcaaaa tgaatcccgt cggctctatc 900 agtttcatta cgtgaactgg ccagaccatg atgttccttc gtcatttgat tctattctgg 960 acatgataag cttaatgagg aaataccaag aacatgaaga tgtgcctatt tgtattcatt 1020 gcagtgcagg ctgtggacga acaggtgcta tttgtgccat agattacacg tggaacttac 1080 tgaaagcagg gaaaattcca gaggaattta atgtatttaa tttaatacaa gaaatgagaa 1140 cacagaggca ctcggcagta caaacaaagg agcagtatga acttgttcat agggctattg 1200 ctcaactgtt tgaaaaacag ctacaactgt atgaaattca tggagcacag aagatccgtg 1260 atggtaatga aattaccact ggaactatgg tcagttccat tgatagcgag aagcaagact 1320 ctcctccgcc aaagccaccg cggactcgaa gttgccttgt agaaggggat gccaaggaag 1380 aaatactaca gccaccagaa cctcacccgg tgccacccat cctgacgcca tcacctcctt 1440 cagccttccc aaccgttacc actgtgtggc aggacagtga caggtaccac ccaaagccag 1500 tgctgcacat ggcctcacca gagcaacacc cagccgacct caacagaagc tatgataaat 1560 cagcggacca atggggaaaa agtgaatcag ctattgagca catagataag aagttagagc 1620 gcaatttaag ttttgagatt aagaaagtcc ctctccaaga agggcccaaa agttttgatg 1680 ggaacacact cttgaatagg ggacatgcga ttaaaattaa atctgcttca tcttctgtag 1740 ttgacagaac ctctaaacca caggagttaa gtgcaggtgc cctaaaggtt gatgatgtat 1800 ctcagaattc ttgcgcggac tgtagtgcgg ctcattcaca cagagctgct gagtcgtcag 1860 aggagtccca gagcaactca cacacacctc cacggccaga ctgcttgcct ctcgataaga 1920 aaggacacgt aacgtggtca cttcatggac ctgaaaatgc cacacctgta cccgactcac 1980 ctgacggcaa atccccagat aatcattctc agactctgaa aaccgtgagt tccacaccca 2040 actccaccgc agaagaggaa gcccacgatc ttacagagca ccacaacagc tcccctctgt 2100 tgaaagctcc cctcagcttt accaaccctc ttcactctga cgactggcac tcagacggag 2160 ggagctctga tggtgctgtg accaggaaca aaactagcat ttcaacagca agtgccacag 2220 tgtctcctgc cagtagtgct gagagtgctt gccataggag agtattgccg atgtccattg 2280 ccagacagga agtagcaggc acgccgcatt caggtgctga gaaagatgct gatgttagtg 2340 aggagtcgcc tcctccttta cctgaacgaa ctcctgagtc ttttgtatta gcagatatgc 2400 ctgtaagacc tgagtggcat gaacttccaa atcaggagtg gtctgaacaa agggaatctg 2460 aaggcttgac aacctctgga aatgaaaaac atgatgcagg gggcatccac acagaggctt 2520 ctgcagactc tccacctgct ttcagtgaca agaaagatca aataacaaaa agtccagcag 2580 aagtcacaga tattggtttt ggtaatcgct gtggaaaacc taaaggacca agagagccac 2640 cttcagaatg gacatgatgc agggagtgaa aggaca 2676 <210> SEQ ID NO 75 <211> LENGTH: 775 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 75 Met Glu Gln Val Glu Ile Leu Arg Arg Phe Ile Gln Arg Val Gln Ala 1 5 10 15 Met Lys Ser Pro Asp His Asn Gly Glu Asp Asn Phe Ala Arg Asp Phe 20 25 30 Met Arg Leu Arg Arg Leu Ser Thr Lys Tyr Arg Thr Glu Lys Ile Tyr 35 40 45 Pro Thr Ala Thr Gly Glu Lys Glu Glu Asn Val Lys Lys Asn Arg Tyr 50 55 60 Lys Asp Ile Leu Pro Phe Asp His Ser Arg Val Lys Leu Thr Leu Lys 65 70 75 80 Thr Pro Ser Gln Asp Ser Asp Tyr Ile Asn Ala Asn Phe Ile Lys Gly 85 90 95 Val Tyr Gly Pro Lys Ala Tyr Val Ala Thr Gln Gly Pro Phe Arg Asn 100 105 110 Thr Val Ile Asp Phe Trp Arg Met Ile Trp Glu Tyr Asn Val Val Met 115 120 125 Ile Val Met Ala Cys Arg Glu Phe Glu Met Gly Arg Lys Lys Cys Glu 130 135 140 Arg Tyr Trp Pro Leu Tyr Gly Glu Asp Pro Ile Thr Phe Ala Pro Phe 145 150 155 160 Lys Ile Ser Cys Glu Asn Glu Gln Ala Arg Thr Asp Tyr Phe Ile Arg 165 170 175 Thr Leu Leu Leu Glu Phe Gln Asn Glu Ser Arg Arg Leu Tyr Gln Phe 180 185 190 His Tyr Val Asn Trp Pro Asp His Asp Val Pro Ser Ser Phe Asp Ser 195 200 205 Ile Leu Asp Met Ile Ser Leu Met Arg Lys Tyr Gln Glu His Glu Asp 210 215 220 Val Pro Ile Cys Ile His Cys Ser Ala Gly Cys Gly Arg Thr Gly Ala 225 230 235 240 Ile Cys Ala Ile Asp Tyr Thr Trp Asn Leu Leu Lys Ala Gly Lys Ile 245 250 255 Pro Glu Glu Phe Asn Val Phe Asn Leu Ile Gln Glu Met Arg Thr Gln 260 265 270 Arg His Ser Ala Val Gln Thr Lys Glu Gln Tyr Glu Leu Val His Arg 275 280 285 Ala Ile Ala Gln Leu Phe Glu Lys Gln Leu Gln Leu Tyr Glu Ile His 290 295 300 Gly Ala Gln Lys Ile Arg Asp Gly Asn Glu Ile Thr Thr Gly Thr Met 305 310 315 320 Val Ser Ser Ile Asp Ser Glu Lys Gln Asp Ser Pro Pro Pro Lys Pro 325 330 335 Pro Arg Thr Arg Ser Cys Leu Val Glu Gly Asp Ala Lys Glu Glu Ile 340 345 350 Leu Gln Pro Pro Glu Pro His Pro Val Pro Pro Ile Leu Thr Pro Ser 355 360 365 Pro Pro Ser Ala Phe Pro Thr Val Thr Thr Val Trp Gln Asp Ser Asp 370 375 380 Arg Tyr His Pro Lys Pro Val Leu His Met Ala Ser Pro Glu Gln His 385 390 395 400 Pro Ala Asp Leu Asn Arg Ser Tyr Asp Lys Ser Ala Asp Gln Trp Gly 405 410 415 Lys Ser Glu Ser Ala Ile Glu His Ile Asp Lys Lys Leu Glu Arg Asn 420 425 430 Leu Ser Phe Glu Ile Lys Lys Val Pro Leu Gln Glu Gly Pro Lys Ser 435 440 445 Phe Asp Gly Asn Thr Leu Leu Asn Arg Gly His Ala Ile Lys Ile Lys 450 455 460 Ser Ala Ser Ser Ser Val Val Asp Arg Thr Ser Lys Pro Gln Glu Leu 465 470 475 480 Ser Ala Gly Ala Leu Lys Val Asp Asp Val Ser Gln Asn Ser Cys Ala 485 490 495 Asp Cys Ser Ala Ala His Ser His Arg Ala Ala Glu Ser Ser Glu Glu 500 505 510 Ser Gln Ser Asn Ser His Thr Pro Pro Arg Pro Asp Cys Leu Pro Leu 515 520 525 Asp Lys Lys Gly His Val Thr Trp Ser Leu His Gly Pro Glu Asn Ala 530 535 540 Thr Pro Val Pro Asp Ser Pro Asp Gly Lys Ser Pro Asp Asn His Ser 545 550 555 560 Gln Thr Leu Lys Thr Val Ser Ser Thr Pro Asn Ser Thr Ala Glu Glu 565 570 575 Glu Ala His Asp Leu Thr Glu His His Asn Ser Ser Pro Leu Leu Lys 580 585 590 Ala Pro Leu Ser Phe Thr Asn Pro Leu His Ser Asp Asp Trp His Ser 595 600 605 Asp Gly Gly Ser Ser Asp Gly Ala Val Thr Arg Asn Lys Thr Ser Ile 610 615 620 Ser Thr Ala Ser Ala Thr Val Ser Pro Ala Ser Ser Ala Glu Ser Ala 625 630 635 640 Cys His Arg Arg Val Leu Pro Met Ser Ile Ala Arg Gln Glu Val Ala 645 650 655 Gly Thr Pro His Ser Gly Ala Glu Lys Asp Ala Asp Val Ser Glu Glu 660 665 670 Ser Pro Pro Pro Leu Pro Glu Arg Thr Pro Glu Ser Phe Val Leu Ala 675 680 685 Asp Met Pro Val Arg Pro Glu Trp His Glu Leu Pro Asn Gln Glu Trp 690 695 700 Ser Glu Gln Arg Glu Ser Glu Gly Leu Thr Thr Ser Gly Asn Glu Lys 705 710 715 720 His Asp Ala Gly Gly Ile His Thr Glu Ala Ser Ala Asp Ser Pro Pro 725 730 735 Ala Phe Ser Asp Lys Lys Asp Gln Ile Thr Lys Ser Pro Ala Glu Val 740 745 750 Thr Asp Ile Gly Phe Gly Asn Arg Cys Gly Lys Pro Lys Gly Pro Arg 755 760 765 Glu Pro Pro Ser Glu Trp Thr 770 775 <210> SEQ ID NO 76 <211> LENGTH: 1608 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 76 ccggccggtg ccgctggcag ccgctagccg cctcgctgct ggcggtggta gggtagggcg 60 gtgctcggag cgagctgggg aagacggagc gggcgctgcg gcgcgcgggc gggcggcggg 120 ggggacgcgg gaggatggag caagtggaga ttctgaggag gttcatccag agggtccagg 180 ccatgaaaag tccggaccac aatggggagg acaacttcgc ccgggacttc atgcgattga 240 gaagattgtc taccaaatat agaacagaaa agatttatcc cacagccact ggagaaaaag 300 aagaaaatgt taaaaagaac agatataagg acatactgcc atttgatcac agccgagtta 360 agttgacttt gaagacacca tcccaagatt cagattatat caatgcaaat tttattaagg 420 gtgtatatgg gccgagagca tacgtggcaa cccaagggcc tttggcgaat acagtcatag 480 acttctggag gatgatatgg gagtacaatg tggtgatcat tgtaatggcc tgtcgtgaat 540 ttgagatggg aaggaaaaag tgtgagcgct attggccttt gtatggagaa gatcctataa 600 catttgcacc atttaaaatt tcttgtgaaa atgaacaagc aagaacagac tacttcattc 660 gaacactttt acttgaattt caaaatgaat cccgtcgact ctatcagttt cattacgtga 720 actggccaga ccatgatgtc ccttcgtcat tcgattctat cctggacatg ataagtctaa 780 tgaggaagta ccaagagcac gaagatgtgc ctatttgtat ccattgcagt gcaggctgtg 840 gacggacagg tgctatttgt gccatcgact acacgtggaa cttactgaaa gcagggaaaa 900 ttccagagga atttaatgta tttaatttaa tacaagaaat gagaacacaa aggcactctg 960 cagtacaaac gaaggagcag tatgaactcg tccatagagc tattgcccaa ctgtttgaaa 1020 aacagctaca actgtatgaa atccacggag cccagaaaat cactgatggt aatgaaatta 1080 gcactggaaa catggtcagt tccattgata gtgaaaaaca agattctcct cctccaaagc 1140 caccacggac tcgaagttgt cttgtagagg gggatgccaa ggaagaaatc ctccagccac 1200 cagagcctca cccggtgccg cccatcctga caccgtcgcc tccttcagca ttcccaacgt 1260 tacactgtgt ggcaagacag tgacaggtac cacccaaagc cagtgctgca catggcttcc 1320 ccagagcagc ccccaacgga cctcaacaga aactatgata agtcagcgga cctaatgggg 1380 agaagcgaat ctgctgttga gcacacagat aaaaagttag aacaaaattt aagttttgag 1440 attaagaaag tccctctcca agaagggccc aaaagttttg atgggaacac actcttgaat 1500 aggggacatg cgattaaaat taagtctgct tcatcttctg tagttgacaa aagctctaag 1560 ccacaggagt taagttcagg tgatctaaag gttcacgatg tgtctcag 1608 <210> SEQ ID NO 77 <211> LENGTH: 382 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 77 Met Glu Gln Val Glu Ile Leu Arg Arg Phe Ile Gln Arg Val Gln Ala 1 5 10 15 Met Lys Ser Pro Asp His Asn Gly Glu Asp Asn Phe Ala Arg Asp Phe 20 25 30 Met Arg Leu Arg Arg Leu Ser Thr Lys Tyr Arg Thr Glu Lys Ile Tyr 35 40 45 Pro Thr Ala Thr Gly Glu Lys Glu Glu Asn Val Lys Lys Asn Arg Tyr 50 55 60 Lys Asp Ile Leu Pro Phe Asp His Ser Arg Val Lys Leu Thr Leu Lys 65 70 75 80 Thr Pro Ser Gln Asp Ser Asp Tyr Ile Asn Ala Asn Phe Ile Lys Gly 85 90 95 Val Tyr Gly Pro Arg Ala Tyr Val Ala Thr Gln Gly Pro Leu Ala Asn 100 105 110 Thr Val Ile Asp Phe Trp Arg Met Ile Trp Glu Tyr Asn Val Val Ile 115 120 125 Ile Val Met Ala Cys Arg Glu Phe Glu Met Gly Arg Lys Lys Cys Glu 130 135 140 Arg Tyr Trp Pro Leu Tyr Gly Glu Asp Pro Ile Thr Phe Ala Pro Phe 145 150 155 160 Lys Ile Ser Cys Glu Asn Glu Gln Ala Arg Thr Asp Tyr Phe Ile Arg 165 170 175 Thr Leu Leu Leu Glu Phe Gln Asn Glu Ser Arg Arg Leu Tyr Gln Phe 180 185 190 His Tyr Val Asn Trp Pro Asp His Asp Val Pro Ser Ser Phe Asp Ser 195 200 205 Ile Leu Asp Met Ile Ser Leu Met Arg Lys Tyr Gln Glu His Glu Asp 210 215 220 Val Pro Ile Cys Ile His Cys Ser Ala Gly Cys Gly Arg Thr Gly Ala 225 230 235 240 Ile Cys Ala Ile Asp Tyr Thr Trp Asn Leu Leu Lys Ala Gly Lys Ile 245 250 255 Pro Glu Glu Phe Asn Val Phe Asn Leu Ile Gln Glu Met Arg Thr Gln 260 265 270 Arg His Ser Ala Val Gln Thr Lys Glu Gln Tyr Glu Leu Val His Arg 275 280 285 Ala Ile Ala Gln Leu Phe Glu Lys Gln Leu Gln Leu Tyr Glu Ile His 290 295 300 Gly Ala Gln Lys Ile Thr Asp Gly Asn Glu Ile Ser Thr Gly Asn Met 305 310 315 320 Val Ser Ser Ile Asp Ser Glu Lys Gln Asp Ser Pro Pro Pro Lys Pro 325 330 335 Pro Arg Thr Arg Ser Cys Leu Val Glu Gly Asp Ala Lys Glu Glu Ile 340 345 350 Leu Gln Pro Pro Glu Pro His Pro Val Pro Pro Ile Leu Thr Pro Ser 355 360 365 Pro Pro Ser Ala Phe Pro Thr Leu His Cys Val Ala Arg Gln 370 375 380 <210> SEQ ID NO 78 <211> LENGTH: 4315 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 ggaaattgtt cctcgtctga taagacaaca gtggagaaag gacgcatgct gtttcttagg 60 gacacggctg gcttccagat atgaccatgt atttgtggct taaactcttg gcatttggct 120 ttgcctttct ggacacagaa gtatttgtga cagggcaaag cccaacacct tcccccactg 180 gattgactac agcaaagatg cccagtgttc cactttcaag tgacccctta cctactcaca 240 ccactgcatt ctcacccgca agcacctttg aaagagaaaa tgacttctca gagaccacaa 300 cttctcttag tccagacaat acttccaccc aagtatcccc ggactctttg gataatgcta 360 gtgcttttaa taccacaggt gtttcatcag tacagacgcc tcaccttccc acgcacgcag 420 actcgcagac gccctctgct ggaactgaca cgcagacatt cagcggctcc gccgccaatg 480 caaaactcaa ccctacccca ggcagcaatg ctatctcaga tgtcccagga gagaggagta 540 cagccagcac ctttcctaca gacccagttt ccccattgac aaccaccctc agccttgcac 600 accacagctc tgctgcctta cctgcacgca cctccaacac caccatcaca gcgaacacct 660 cagatgccta ccttaatgcc tctgaaacaa ccactctgag cccttctgga agcgctgtca 720 tttcaaccac aacaatagct actactccat ctaagccaac atgtgatgaa aaatatgcaa 780 acatcactgt ggattactta tataacaagg aaactaaatt atttacagca aagctaaatg 840 ttaatgagaa tgtggaatgt ggaaacaata cttgcacaaa caatgaggtg cataacctta 900 cagaatgtaa aaatgcgtct gtttccatat ctcataattc atgtactgct cctgataaga 960 cattaatatt agatgtgcca ccaggggttg aaaagtttca gttacatgat tgtacacaag 1020 ttgaaaaagc agatactact atttgtttaa aatggaaaaa tattgaaacc tttacttgtg 1080 atacacagaa tattacctac agatttcagt gtggtaatat gatatttgat aataaagaaa 1140 ttaaattaga aaaccttgaa cccgaacatg agtataagtg tgactcagaa atactctata 1200 ataaccacaa gtttactaac gcaagtaaaa ttattaaaac agattttggg agtccaggag 1260 agcctcagat tattttttgt agaagtgaag ctgcacatca aggagtaatt acctggaatc 1320 cccctcaaag atcatttcat aattttaccc tctgttatat aaaagagaca gaaaaagatt 1380 gcctcaatct ggataaaaac ctgatcaaat atgatttgca aaatttaaaa ccttatacga 1440 aatatgtttt atcattacat gcctacatca ttgcaaaagt gcaacgtaat ggaagtgctg 1500 caatgtgtca tttcacaact aaaagtgctc ctccaagcca ggtctggaac atgactgtct 1560 ccatgacatc agataatagt atgcatgtca agtgtaggcc tcccagggac cgtaatggcc 1620 cccatgaacg ttaccatttg gaagttgaag ctggaaatac tctggttaga aatgagtcgc 1680 ataagaattg cgatttccgt gtaaaagatc ttcaatattc aacagactac acttttaagg 1740 cctattttca caatggagac tatcctggag aaccctttat tttacatcat tcaacatctt 1800 ataattctaa ggcactgata gcatttctgg catttctgat tattgtgaca tcaatagccc 1860 tgcttgttgt tctctacaaa atctatgatc tacataagaa aagatcctgc aatttagatg 1920 aacagcagga gcttgttgaa agggatgatg aaaaacaact gatgaatgtg gagccaatcc 1980 atgcagatat tttgttggaa acttataaga ggaagattgc tgatgaagga agaccttttc 2040 tggctgaatt tcagagcatc ccgcgggtgt tcagcaagtt tcctataaag gaagctcgaa 2100 agccctttaa ccagaataaa aaccgttatg ttgacattct tccttatgat tataaccgtg 2160 ttgaactctc tgagataaac ggagatgcag ggtcaaacta cataaatgcc agctatattg 2220 atggtttcaa agaacccagg aaatacattg ctgcacaagg tcccagggat gaaactgttg 2280 atgatttctg gaggatgatt tgggaacaga aagccacagt tattgtcatg gtcactcgat 2340 gtgaagaagg aaacaggaac aagtgtgcag aatactggcc gtcaatggaa gagggcactc 2400 gggcttttgg agatgttgtt gtaaagatca accagcacaa aagatgtcca gattacatca 2460 ttcagaaatt gaacattgta aataaaaaag aaaaagcaac tggaagagag gtgactcaca 2520 ttcagttcac cagctggcca gaccacgggg tgcctgagga tcctcacttg ctcctcaaac 2580 tgagaaggag agtgaatgcc ttcagcaatt tcttcagtgg tcccattgtg gtgcactgca 2640 gtgctggtgt tgggcgcaca ggaacctata tcggaattga tgccatgcta gaaggcttgg 2700 aagccgagaa caaagtggat gtttatggtt atgttgtcaa gctaaggcga cagagatgcc 2760 tgatggttca agtagaggcc cagtacatct tgatccatca ggctttggtg gaatacaatc 2820 agtttggaga aacagaagtg aatttgtctg aattacatcc atatctacat aacatgaaga 2880 aaagggatcc acccagtgag ccgtctccac tagaggctga attccagaga cttccttcat 2940 ataggagctg gaggacacag cacattggaa atcaagaaga aaataaaagt aaaaacagga 3000 attctaatgt catcccatat gactataaca gagtgccact taaacatgag ctggaaatga 3060 gtaaagagag tgagcatgat tcagatgaat cctctgatga tgacagtgat tcagaggaac 3120 caagcaaata catcaatgca tcttttataa tgagctactg gaaacctgaa gtgatgattg 3180 ctgctcaggg accactgaag gagaccattg gtgacttttg gcagatgatc ttccaaagaa 3240 aagtcaaagt tattgttatg ctgacagaac tgaaacatgg agaccaggaa atctgtgctc 3300 agtactgggg agaaggaaag caaacatatg gagatattga agttgacctg aaagacacag 3360 acaaatcttc aacttatacc cttcgtgtct ttgaactgag acattccaag aggaaagact 3420 ctcgaactgt gtaccagtac caatatacaa actggagtgt ggagcagctt cctgcagaac 3480 ccaaggaatt aatctctatg attcaggtcg tcaaacaaaa acttccccag aagaattcct 3540 ctgaagggaa caagcatcac aagagtacac ctctactcat tcactgcagg gatggatctc 3600 agcaaacggg aatattttgt gctttgttaa atctcttaga aagtgcggaa acagaagagg 3660 tagtggatat ttttcaagtg gtaaaagctc tacgcaaagc taggctaggc atggtttcca 3720 cattcgagca atatcaattc ctatatgacg tcattgccag cacctaccct gctcagaatg 3780 gacaagtaaa gaaaaacaac catcaagaag ataaaattga atttgataat gaagtggaca 3840 aagtaaagca ggatgctaat tgtgttaatc cacttggtgc cccagaaaag ctccctgaag 3900 caaaggaaca ggctgaaggt tctgaaccca cgagtggcac tgaggggcca gaacattctg 3960 tcaatggtcc tgcaagtcca gctttaaatc aaggttcata ggaaaagaca taaatgagga 4020 aactccaaac ctcctgttag ctgttatttc tatttttgta gaagtaggaa gtgaaaatag 4080 gtatacagtg gattaattaa atgcagcgaa ccaatatttg tagaagggtt atattttact 4140 actgtggaaa aatatttaag atagttttgc cagaacagtt tgtacagacg tatgcttatt 4200 ttaaaatttt atctcttatt cagtaaaaaa caacttcttt gtaatcgtta tgagtgtata 4260 tgtatgtgtg tatgggtgtg tgtttgtgtg agagacagag aaagagagag aattc 4315 <210> SEQ ID NO 79 <211> LENGTH: 1304 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 79 Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe Leu Asp 1 5 10 15 Thr Glu Val Phe Val Thr Gly Gln Ser Pro Thr Pro Ser Pro Thr Gly 20 25 30 Leu Thr Thr Ala Lys Met Pro Ser Val Pro Leu Ser Ser Asp Pro Leu 35 40 45 Pro Thr His Thr Thr Ala Phe Ser Pro Ala Ser Thr Phe Glu Arg Glu 50 55 60 Asn Asp Phe Ser Glu Thr Thr Thr Ser Leu Ser Pro Asp Asn Thr Ser 65 70 75 80 Thr Gln Val Ser Pro Asp Ser Leu Asp Asn Ala Ser Ala Phe Asn Thr 85 90 95 Thr Gly Val Ser Ser Val Gln Thr Pro His Leu Pro Thr His Ala Asp 100 105 110 Ser Gln Thr Pro Ser Ala Gly Thr Asp Thr Gln Thr Phe Ser Gly Ser 115 120 125 Ala Ala Asn Ala Lys Leu Asn Pro Thr Pro Gly Ser Asn Ala Ile Ser 130 135 140 Asp Val Pro Gly Glu Arg Ser Thr Ala Ser Thr Phe Pro Thr Asp Pro 145 150 155 160 Val Ser Pro Leu Thr Thr Thr Leu Ser Leu Ala His His Ser Ser Ala 165 170 175 Ala Leu Pro Ala Arg Thr Ser Asn Thr Thr Ile Thr Ala Asn Thr Ser 180 185 190 Asp Ala Tyr Leu Asn Ala Ser Glu Thr Thr Thr Leu Ser Pro Ser Gly 195 200 205 Ser Ala Val Ile Ser Thr Thr Thr Ile Ala Thr Thr Pro Ser Lys Pro 210 215 220 Thr Cys Asp Glu Lys Tyr Ala Asn Ile Thr Val Asp Tyr Leu Tyr Asn 225 230 235 240 Lys Glu Thr Lys Leu Phe Thr Ala Lys Leu Asn Val Asn Glu Asn Val 245 250 255 Glu Cys Gly Asn Asn Thr Cys Thr Asn Asn Glu Val His Asn Leu Thr 260 265 270 Glu Cys Lys Asn Ala Ser Val Ser Ile Ser His Asn Ser Cys Thr Ala 275 280 285 Pro Asp Lys Thr Leu Ile Leu Asp Val Pro Pro Gly Val Glu Lys Phe 290 295 300 Gln Leu His Asp Cys Thr Gln Val Glu Lys Ala Asp Thr Thr Ile Cys 305 310 315 320 Leu Lys Trp Lys Asn Ile Glu Thr Phe Thr Cys Asp Thr Gln Asn Ile 325 330 335 Thr Tyr Arg Phe Gln Cys Gly Asn Met Ile Phe Asp Asn Lys Glu Ile 340 345 350 Lys Leu Glu Asn Leu Glu Pro Glu His Glu Tyr Lys Cys Asp Ser Glu 355 360 365 Ile Leu Tyr Asn Asn His Lys Phe Thr Asn Ala Ser Lys Ile Ile Lys 370 375 380 Thr Asp Phe Gly Ser Pro Gly Glu Pro Gln Ile Ile Phe Cys Arg Ser 385 390 395 400 Glu Ala Ala His Gln Gly Val Ile Thr Trp Asn Pro Pro Gln Arg Ser 405 410 415 Phe His Asn Phe Thr Leu Cys Tyr Ile Lys Glu Thr Glu Lys Asp Cys 420 425 430 Leu Asn Leu Asp Lys Asn Leu Ile Lys Tyr Asp Leu Gln Asn Leu Lys 435 440 445 Pro Tyr Thr Lys Tyr Val Leu Ser Leu His Ala Tyr Ile Ile Ala Lys 450 455 460 Val Gln Arg Asn Gly Ser Ala Ala Met Cys His Phe Thr Thr Lys Ser 465 470 475 480 Ala Pro Pro Ser Gln Val Trp Asn Met Thr Val Ser Met Thr Ser Asp 485 490 495 Asn Ser Met His Val Lys Cys Arg Pro Pro Arg Asp Arg Asn Gly Pro 500 505 510 His Glu Arg Tyr His Leu Glu Val Glu Ala Gly Asn Thr Leu Val Arg 515 520 525 Asn Glu Ser His Lys Asn Cys Asp Phe Arg Val Lys Asp Leu Gln Tyr 530 535 540 Ser Thr Asp Tyr Thr Phe Lys Ala Tyr Phe His Asn Gly Asp Tyr Pro 545 550 555 560 Gly Glu Pro Phe Ile Leu His His Ser Thr Ser Tyr Asn Ser Lys Ala 565 570 575 Leu Ile Ala Phe Leu Ala Phe Leu Ile Ile Val Thr Ser Ile Ala Leu 580 585 590 Leu Val Val Leu Tyr Lys Ile Tyr Asp Leu His Lys Lys Arg Ser Cys 595 600 605 Asn Leu Asp Glu Gln Gln Glu Leu Val Glu Arg Asp Asp Glu Lys Gln 610 615 620 Leu Met Asn Val Glu Pro Ile His Ala Asp Ile Leu Leu Glu Thr Tyr 625 630 635 640 Lys Arg Lys Ile Ala Asp Glu Gly Arg Pro Phe Leu Ala Glu Phe Gln 645 650 655 Ser Ile Pro Arg Val Phe Ser Lys Phe Pro Ile Lys Glu Ala Arg Lys 660 665 670 Pro Phe Asn Gln Asn Lys Asn Arg Tyr Val Asp Ile Leu Pro Tyr Asp 675 680 685 Tyr Asn Arg Val Glu Leu Ser Glu Ile Asn Gly Asp Ala Gly Ser Asn 690 695 700 Tyr Ile Asn Ala Ser Tyr Ile Asp Gly Phe Lys Glu Pro Arg Lys Tyr 705 710 715 720 Ile Ala Ala Gln Gly Pro Arg Asp Glu Thr Val Asp Asp Phe Trp Arg 725 730 735 Met Ile Trp Glu Gln Lys Ala Thr Val Ile Val Met Val Thr Arg Cys 740 745 750 Glu Glu Gly Asn Arg Asn Lys Cys Ala Glu Tyr Trp Pro Ser Met Glu 755 760 765 Glu Gly Thr Arg Ala Phe Gly Asp Val Val Val Lys Ile Asn Gln His 770 775 780 Lys Arg Cys Pro Asp Tyr Ile Ile Gln Lys Leu Asn Ile Val Asn Lys 785 790 795 800 Lys Glu Lys Ala Thr Gly Arg Glu Val Thr His Ile Gln Phe Thr Ser 805 810 815 Trp Pro Asp His Gly Val Pro Glu Asp Pro His Leu Leu Leu Lys Leu 820 825 830 Arg Arg Arg Val Asn Ala Phe Ser Asn Phe Phe Ser Gly Pro Ile Val 835 840 845 Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr Tyr Ile Gly Ile 850 855 860 Asp Ala Met Leu Glu Gly Leu Glu Ala Glu Asn Lys Val Asp Val Tyr 865 870 875 880 Gly Tyr Val Val Lys Leu Arg Arg Gln Arg Cys Leu Met Val Gln Val 885 890 895 Glu Ala Gln Tyr Ile Leu Ile His Gln Ala Leu Val Glu Tyr Asn Gln 900 905 910 Phe Gly Glu Thr Glu Val Asn Leu Ser Glu Leu His Pro Tyr Leu His 915 920 925 Asn Met Lys Lys Arg Asp Pro Pro Ser Glu Pro Ser Pro Leu Glu Ala 930 935 940 Glu Phe Gln Arg Leu Pro Ser Tyr Arg Ser Trp Arg Thr Gln His Ile 945 950 955 960 Gly Asn Gln Glu Glu Asn Lys Ser Lys Asn Arg Asn Ser Asn Val Ile 965 970 975 Pro Tyr Asp Tyr Asn Arg Val Pro Leu Lys His Glu Leu Glu Met Ser 980 985 990 Lys Glu Ser Glu His Asp Ser Asp Glu Ser Ser Asp Asp Asp Ser Asp 995 1000 1005 Ser Glu Glu Pro Ser Lys Tyr Ile Asn Ala Ser Phe Ile Met Ser Tyr 1010 1015 1020 Trp Lys Pro Glu Val Met Ile Ala Ala Gln Gly Pro Leu Lys Glu Thr 1025 1030 1035 1040 Ile Gly Asp Phe Trp Gln Met Ile Phe Gln Arg Lys Val Lys Val Ile 1045 1050 1055 Val Met Leu Thr Glu Leu Lys His Gly Asp Gln Glu Ile Cys Ala Gln 1060 1065 1070 Tyr Trp Gly Glu Gly Lys Gln Thr Tyr Gly Asp Ile Glu Val Asp Leu 1075 1080 1085 Lys Asp Thr Asp Lys Ser Ser Thr Tyr Thr Leu Arg Val Phe Glu Leu 1090 1095 1100 Arg His Ser Lys Arg Lys Asp Ser Arg Thr Val Tyr Gln Tyr Gln Tyr 1105 1110 1115 1120 Thr Asn Trp Ser Val Glu Gln Leu Pro Ala Glu Pro Lys Glu Leu Ile 1125 1130 1135 Ser Met Ile Gln Val Val Lys Gln Lys Leu Pro Gln Lys Asn Ser Ser 1140 1145 1150 Glu Gly Asn Lys His His Lys Ser Thr Pro Leu Leu Ile His Cys Arg 1155 1160 1165 Asp Gly Ser Gln Gln Thr Gly Ile Phe Cys Ala Leu Leu Asn Leu Leu 1170 1175 1180 Glu Ser Ala Glu Thr Glu Glu Val Val Asp Ile Phe Gln Val Val Lys 1185 1190 1195 1200 Ala Leu Arg Lys Ala Arg Leu Gly Met Val Ser Thr Phe Glu Gln Tyr 1205 1210 1215 Gln Phe Leu Tyr Asp Val Ile Ala Ser Thr Tyr Pro Ala Gln Asn Gly 1220 1225 1230 Gln Val Lys Lys Asn Asn His Gln Glu Asp Lys Ile Glu Phe Asp Asn 1235 1240 1245 Glu Val Asp Lys Val Lys Gln Asp Ala Asn Cys Val Asn Pro Leu Gly 1250 1255 1260 Ala Pro Glu Lys Leu Pro Glu Ala Lys Glu Gln Ala Glu Gly Ser Glu 1265 1270 1275 1280 Pro Thr Ser Gly Thr Glu Gly Pro Glu His Ser Val Asn Gly Pro Ala 1285 1290 1295 Ser Pro Ala Leu Asn Gln Gly Ser 1300 <210> SEQ ID NO 80 <211> LENGTH: 4597 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 80 cgacatttta actgaactgc gggataaagt gaaatctttc cgtgcagctc tacgagagga 60 ggaaattgtt cctcgtctga taagacaaca gtggagaaag gacgcatgct gtttcttagg 120 gacacggctg acttccagat atgaccatgt atttgtggct taaactcttg gcatttggct 180 ttgcctttct ggacacagaa gtatttgtga cagggcaaag cccaacacct tcccccactg 240 atgcctacct taatgcctct gaaacaacca ctctgagccc ttctggaagc gctgtcattt 300 caaccacaac aatagctact actccatcta agccaacatg tgatgaaaaa tatgcaaaca 360 tcactgtgga ttacttatat aacaaggaaa ctaaattatt tacagcaaag ctaaatgtta 420 atgagaatgt ggaatgtgga aacaatactt gcacaaacaa tgaggtgcat aaccttacag 480 aatgtaaaaa tgcgtctgtt tccatatctc ataattcatg tactgctcct gataagacat 540 taatattaga tgtgccacca ggggttgaaa agtttcagtt acatgattgt acacaagttg 600 aaaaagcaga tactactatt tgtttaaaat ggaaaaatat tgaaaccttt acttgtgata 660 cacagaatat tacctacaga tttcagtgtg gtaatatgat atttgataat aaagaaatta 720 aattagaaaa ccttgaaccc gaacatgagt ataagtgtga ctcagaaata ctctataata 780 accacaagtt tactaacgca agtaaaatta ttaaaacaga ttttgggagt ccaggagagc 840 ctcagattat tttttgtaga agtgaagctg cacatcaagg agtaattacc tggaatcccc 900 ctcaaagatc atttcataat tttaccctct gttatataaa agagacagaa aaagattgcc 960 tcaatctgga taaaaacctg atcaaatatg atttgcaaaa tttaaaacct tatacgaaat 1020 atgttttatc attacatgcc tacatcattg caaaagtgca acgtaatgga agtgctgcaa 1080 tgtgtcattt cacaactaaa agtgctcctc caagccaggt ctggaacatg actgtctcca 1140 tgacatcaga taatagtatg catgtcaagt gtaggcctcc cagggaccgt aatggccccc 1200 atgaacgtta ccatttggaa gttgaagctg gaaatactct ggttagaaat gagtcgcata 1260 agaattgcga tttccgtgta aaagatcttc aatattcaac agactacact tttaaggcct 1320 attttcacaa tggagactat cctggagaac cctttatttt acatcattca acatcttata 1380 attctaaggc actgatagca tttctggcat ttctgattat tgtgacatca atagccctgc 1440 ttgttgttct ctacaaaatc tatgatctac ataagaaaag atcctgcaat ttagatgaac 1500 agcaggagct tgttgaaagg gatgatgaaa aacaactgat gaatgtggag ccaatccatg 1560 cagatatttt gttggaaact tataagagga agattgctga tgaaggaaga ctttttctgg 1620 ctgaatttca gagcatcccg cgggtgttca gcaagtttcc tataaaggaa gctcgaaagc 1680 cctttaacca gaataaaaac cgttatgttg acattcttcc ttatgattat aaccgtgttg 1740 aactctctga gataaacgga gatgcagggt caaactacat aaatgccagc tatattgatg 1800 gtttcaaaga acccaggaaa tacattgctg cacaaggtcc cagggatgaa actgttgatg 1860 atttctggag gatgatttgg gaacagaaag ccacagttat tgtcatggtc actcgatgtg 1920 aagaaggaaa caggaacaag tgtgcagaat actggccgtc aatggaagag ggcactcggg 1980 cttttggaga tgttgttgta aagatcaacc agcacaaaag atgtccagat tacatcattc 2040 agaaattgaa cattgtaaat aaaaaagaaa aagcaactgg aagagaggtg actcacattc 2100 agttcaccag ctggccagac cacggggtgc ctgaggatcc tcacttgctc ctcaaactga 2160 gaaggagagt gaatgccttc agcaatttct tcagtggtcc cattgtggtg cactgcagtg 2220 ctggtgttgg gcgcacagga acctatatcg gaattgatgc catgctagaa ggcctggaag 2280 ccgagaacaa agtggatgtt tatggttatg ttgtcaagct aaggcgacag agatgcctga 2340 tggttcaagt agaggcccag tacatcttga tccatcaggc tttggtggaa tacaatcagt 2400 ttggagaaac agaagtgaat ttgtctgaat tacatccata tctacataac atgaagaaaa 2460 gggatccacc cagtgagccg tctccactag aggctgaatt ccagagactt ccttcatata 2520 ggagctggag gacacagcac attggaaatc aagaagaaaa taaaagtaaa aacaggaatt 2580 ctaatgtcat cccatatgac tataacagag tgccacttaa acatgagctg gaaatgagta 2640 aagagagtga gcatgattca gatgaatcct ctgatgatga cagtgattca gaggaaccaa 2700 gcaaatacat caatgcatct tttataatga gctactggaa acctgaagtg atgattgctg 2760 ctcagggacc actgaaggag accattggtg acttttggca gatgatcttc caaagaaaag 2820 tcaaagttat tgttatgctg acagaactga aacatggaga ccaggaaatc tgtgctcagt 2880 actggggaga aggaaagcaa acatatggag atattgaagt tgacctgaaa gacacagaca 2940 aatcttcaac ttataccctt cgtgtctttg aactgagaca ttccaagagg aaagactctc 3000 gaactgtgta ccagtaccaa tatacaaact ggagtgtgga gcagcttcct gcagaaccca 3060 aggaattaat ctctatgatt caggtcgtca aacaaaaact tccccagaag aattcctctg 3120 aagggaacaa gcatcacaag agtacacctc tactcattca ctgcagggat ggatctcagc 3180 aaacgggaat attttgtgct ttgttaaatc tcttagaaag tgcggaaaca gaagaggtag 3240 tggatatttt tcaagtggta aaagctctac gcaaagctag gccaggcatg gtttccacat 3300 tcgagcaata tcaattccta tatgacgtca ttgccagcac ctaccctgct cagaatggac 3360 aagtaaagaa aaacaaccat caagaagata aaattgaatt tgataatgaa gtggacaaag 3420 taaagcagga tgctaattgt gttaatccac ttggtgcccc agaaaagctc cctgaagcaa 3480 aggaacaggc tgaaggttct gaacccacga gtggcactga ggggccagaa cattctgtca 3540 atggtcctgc aagtccagcc ttaaatcaag gttcatagga aaagacataa atgaggaaac 3600 tccaaacctc ctgttagctg ttatttctat ttttgtagaa gtaggaagtg aaaataggta 3660 tacagtggat taattaaatg cagcgaacca atatttgtag aagggttata ttttactact 3720 gtggaaaaat atttaagata gttttgccag aacagtttgt acagacgtat gcttatttta 3780 aaattttatc tcttattcag taaaaaacaa cttctttgta atcgttatgt gtgtatatgt 3840 atgtgtgtat gggtgtgtgt ttgtgtgaga gacagagaaa gagagagaat tctttcaagt 3900 gaatctaaaa gcttttgctt ttcctttgtt tttatgaaga aaaaatacat tttatattag 3960 aagtgttaac ttagcttgaa ggatctgttt ttaaaaatca taaactgtgt gcagactcaa 4020 taaaatcatg tacatttctg aaatgacctc aagatgtcct ccttgttcta ctcatatata 4080 tctatcttat atacttacta ttttacttct agagatagta cataaaggtg gtatgtgtgt 4140 gtatgctact acaaaaaagt tgttaactaa attaacattg ggaaatctta tattccatat 4200 attagcattt agtccaatgt ctttttaagc ttatttaatt aaaaaatttc cagtgagctt 4260 atcatgctgt ctttacatgg ggttttcaat tttgcatgct cgattattcc ctgtacaata 4320 tttaaaattt attgcttgat acttttgaca acaaattagg ttttgtacaa ttgaacttaa 4380 ataaatgtca ttaaaataaa taaatgcaat atgtattaat attcattgta taaaaataga 4440 agaatacaaa catatttgtt aaatatttac atatgaaatt taatatagct atttttatgg 4500 aatttttcat tgatatgaaa aatatgatat tgcatatgca tagttcccat gttaaatccc 4560 attcataact ttcattaaag catttacttt gaatttc 4597 <210> SEQ ID NO 81 <211> LENGTH: 1143 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 81 Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe Leu Asp 1 5 10 15 Thr Glu Val Phe Val Thr Gly Gln Ser Pro Thr Pro Ser Pro Thr Asp 20 25 30 Ala Tyr Leu Asn Ala Ser Glu Thr Thr Thr Leu Ser Pro Ser Gly Ser 35 40 45 Ala Val Ile Ser Thr Thr Thr Ile Ala Thr Thr Pro Ser Lys Pro Thr 50 55 60 Cys Asp Glu Lys Tyr Ala Asn Ile Thr Val Asp Tyr Leu Tyr Asn Lys 65 70 75 80 Glu Thr Lys Leu Phe Thr Ala Lys Leu Asn Val Asn Glu Asn Val Glu 85 90 95 Cys Gly Asn Asn Thr Cys Thr Asn Asn Glu Val His Asn Leu Thr Glu 100 105 110 Cys Lys Asn Ala Ser Val Ser Ile Ser His Asn Ser Cys Thr Ala Pro 115 120 125 Asp Lys Thr Leu Ile Leu Asp Val Pro Pro Gly Val Glu Lys Phe Gln 130 135 140 Leu His Asp Cys Thr Gln Val Glu Lys Ala Asp Thr Thr Ile Cys Leu 145 150 155 160 Lys Trp Lys Asn Ile Glu Thr Phe Thr Cys Asp Thr Gln Asn Ile Thr 165 170 175 Tyr Arg Phe Gln Cys Gly Asn Met Ile Phe Asp Asn Lys Glu Ile Lys 180 185 190 Leu Glu Asn Leu Glu Pro Glu His Glu Tyr Lys Cys Asp Ser Glu Ile 195 200 205 Leu Tyr Asn Asn His Lys Phe Thr Asn Ala Ser Lys Ile Ile Lys Thr 210 215 220 Asp Phe Gly Ser Pro Gly Glu Pro Gln Ile Ile Phe Cys Arg Ser Glu 225 230 235 240 Ala Ala His Gln Gly Val Ile Thr Trp Asn Pro Pro Gln Arg Ser Phe 245 250 255 His Asn Phe Thr Leu Cys Tyr Ile Lys Glu Thr Glu Lys Asp Cys Leu 260 265 270 Asn Leu Asp Lys Asn Leu Ile Lys Tyr Asp Leu Gln Asn Leu Lys Pro 275 280 285 Tyr Thr Lys Tyr Val Leu Ser Leu His Ala Tyr Ile Ile Ala Lys Val 290 295 300 Gln Arg Asn Gly Ser Ala Ala Met Cys His Phe Thr Thr Lys Ser Ala 305 310 315 320 Pro Pro Ser Gln Val Trp Asn Met Thr Val Ser Met Thr Ser Asp Asn 325 330 335 Ser Met His Val Lys Cys Arg Pro Pro Arg Asp Arg Asn Gly Pro His 340 345 350 Glu Arg Tyr His Leu Glu Val Glu Ala Gly Asn Thr Leu Val Arg Asn 355 360 365 Glu Ser His Lys Asn Cys Asp Phe Arg Val Lys Asp Leu Gln Tyr Ser 370 375 380 Thr Asp Tyr Thr Phe Lys Ala Tyr Phe His Asn Gly Asp Tyr Pro Gly 385 390 395 400 Glu Pro Phe Ile Leu His His Ser Thr Ser Tyr Asn Ser Lys Ala Leu 405 410 415 Ile Ala Phe Leu Ala Phe Leu Ile Ile Val Thr Ser Ile Ala Leu Leu 420 425 430 Val Val Leu Tyr Lys Ile Tyr Asp Leu His Lys Lys Arg Ser Cys Asn 435 440 445 Leu Asp Glu Gln Gln Glu Leu Val Glu Arg Asp Asp Glu Lys Gln Leu 450 455 460 Met Asn Val Glu Pro Ile His Ala Asp Ile Leu Leu Glu Thr Tyr Lys 465 470 475 480 Arg Lys Ile Ala Asp Glu Gly Arg Leu Phe Leu Ala Glu Phe Gln Ser 485 490 495 Ile Pro Arg Val Phe Ser Lys Phe Pro Ile Lys Glu Ala Arg Lys Pro 500 505 510 Phe Asn Gln Asn Lys Asn Arg Tyr Val Asp Ile Leu Pro Tyr Asp Tyr 515 520 525 Asn Arg Val Glu Leu Ser Glu Ile Asn Gly Asp Ala Gly Ser Asn Tyr 530 535 540 Ile Asn Ala Ser Tyr Ile Asp Gly Phe Lys Glu Pro Arg Lys Tyr Ile 545 550 555 560 Ala Ala Gln Gly Pro Arg Asp Glu Thr Val Asp Asp Phe Trp Arg Met 565 570 575 Ile Trp Glu Gln Lys Ala Thr Val Ile Val Met Val Thr Arg Cys Glu 580 585 590 Glu Gly Asn Arg Asn Lys Cys Ala Glu Tyr Trp Pro Ser Met Glu Glu 595 600 605 Gly Thr Arg Ala Phe Gly Asp Val Val Val Lys Ile Asn Gln His Lys 610 615 620 Arg Cys Pro Asp Tyr Ile Ile Gln Lys Leu Asn Ile Val Asn Lys Lys 625 630 635 640 Glu Lys Ala Thr Gly Arg Glu Val Thr His Ile Gln Phe Thr Ser Trp 645 650 655 Pro Asp His Gly Val Pro Glu Asp Pro His Leu Leu Leu Lys Leu Arg 660 665 670 Arg Arg Val Asn Ala Phe Ser Asn Phe Phe Ser Gly Pro Ile Val Val 675 680 685 His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr Tyr Ile Gly Ile Asp 690 695 700 Ala Met Leu Glu Gly Leu Glu Ala Glu Asn Lys Val Asp Val Tyr Gly 705 710 715 720 Tyr Val Val Lys Leu Arg Arg Gln Arg Cys Leu Met Val Gln Val Glu 725 730 735 Ala Gln Tyr Ile Leu Ile His Gln Ala Leu Val Glu Tyr Asn Gln Phe 740 745 750 Gly Glu Thr Glu Val Asn Leu Ser Glu Leu His Pro Tyr Leu His Asn 755 760 765 Met Lys Lys Arg Asp Pro Pro Ser Glu Pro Ser Pro Leu Glu Ala Glu 770 775 780 Phe Gln Arg Leu Pro Ser Tyr Arg Ser Trp Arg Thr Gln His Ile Gly 785 790 795 800 Asn Gln Glu Glu Asn Lys Ser Lys Asn Arg Asn Ser Asn Val Ile Pro 805 810 815 Tyr Asp Tyr Asn Arg Val Pro Leu Lys His Glu Leu Glu Met Ser Lys 820 825 830 Glu Ser Glu His Asp Ser Asp Glu Ser Ser Asp Asp Asp Ser Asp Ser 835 840 845 Glu Glu Pro Ser Lys Tyr Ile Asn Ala Ser Phe Ile Met Ser Tyr Trp 850 855 860 Lys Pro Glu Val Met Ile Ala Ala Gln Gly Pro Leu Lys Glu Thr Ile 865 870 875 880 Gly Asp Phe Trp Gln Met Ile Phe Gln Arg Lys Val Lys Val Ile Val 885 890 895 Met Leu Thr Glu Leu Lys His Gly Asp Gln Glu Ile Cys Ala Gln Tyr 900 905 910 Trp Gly Glu Gly Lys Gln Thr Tyr Gly Asp Ile Glu Val Asp Leu Lys 915 920 925 Asp Thr Asp Lys Ser Ser Thr Tyr Thr Leu Arg Val Phe Glu Leu Arg 930 935 940 His Ser Lys Arg Lys Asp Ser Arg Thr Val Tyr Gln Tyr Gln Tyr Thr 945 950 955 960 Asn Trp Ser Val Glu Gln Leu Pro Ala Glu Pro Lys Glu Leu Ile Ser 965 970 975 Met Ile Gln Val Val Lys Gln Lys Leu Pro Gln Lys Asn Ser Ser Glu 980 985 990 Gly Asn Lys His His Lys Ser Thr Pro Leu Leu Ile His Cys Arg Asp 995 1000 1005 Gly Ser Gln Gln Thr Gly Ile Phe Cys Ala Leu Leu Asn Leu Leu Glu 1010 1015 1020 Ser Ala Glu Thr Glu Glu Val Val Asp Ile Phe Gln Val Val Lys Ala 1025 1030 1035 1040 Leu Arg Lys Ala Arg Pro Gly Met Val Ser Thr Phe Glu Gln Tyr Gln 1045 1050 1055 Phe Leu Tyr Asp Val Ile Ala Ser Thr Tyr Pro Ala Gln Asn Gly Gln 1060 1065 1070 Val Lys Lys Asn Asn His Gln Glu Asp Lys Ile Glu Phe Asp Asn Glu 1075 1080 1085 Val Asp Lys Val Lys Gln Asp Ala Asn Cys Val Asn Pro Leu Gly Ala 1090 1095 1100 Pro Glu Lys Leu Pro Glu Ala Lys Glu Gln Ala Glu Gly Ser Glu Pro 1105 1110 1115 1120 Thr Ser Gly Thr Glu Gly Pro Glu His Ser Val Asn Gly Pro Ala Ser 1125 1130 1135 Pro Ala Leu Asn Gln Gly Ser 1140 <210> SEQ ID NO 82 <211> LENGTH: 5007 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 82 ggagacccta tttcttaggg gcacagctga tctccagata tgaccatggg tttgtggctc 60 aaacttctgg cctttggatt tgcccttctg gacacagaag tctttgtcac agggcaaaca 120 cctacaccca gtgatgaact gagcacaaca gagaatgccc ttcttctgcc tcaaagtgac 180 cccttacctg ctcgcaccac tgaatccaca cccccaagca tctctgaaag aggaaatggc 240 tcttcagaga ccacatatca tccaggtgtg ttatccacgc tgctgcctca cctgtcccca 300 cagcctgact cgcagacgcc ctctgccgga ggagctgaca ctcagacatt cagcagccaa 360 gctgacaatc ccacactcac gcctgctccc ggcggcggga ctgacccacc aggtgtgcca 420 ggggagagga ctgtaccggg gaccattcct gcagacacag cctttcctgt tgataccccc 480 agccttgcac gcaacagctc tgctgcctca cctacacaca cctccaatgt cagcaccaca 540 gatatctctt caggtgccag cctcacaact cttacaccat ccactctggg ccttgcaagc 600 actgaccctc caagcacaac catagctacc acaacgaagc aaacatgtgc tgccatgttt 660 gggaacatta ctgtgaatta cacctatgaa tctagtaatc agacttttaa ggcagacctc 720 aaagatgtcc aaaatgctaa gtgtggaaat gaggattgtg aaaacgtgtt aaataatcta 780 gaagaatgct cacagataaa aaacatcagt gtgtctaatg actcatgtgc tccagctaca 840 actatagatt tatatgtacc accagggact gacaagtttt cgctacatga ctgcacacca 900 aaagaaaagg ctaatacttc aatttgtttg gagtggaaaa cagaaaacct tgatttcaga 960 aaatgcaaca gtgacaatat ttcatatgta ctccactgtg agccagaaaa taatacaaaa 1020 tgcattagaa gaaatacatt catacctgaa agatgtcagt tggacaacct tcgtgcccaa 1080 acaaattaca catgtgtagc agaaatctta tatcgcggtg taaaactcgt caaaaatgtt 1140 ataaatgtgc agacagattt ggggattcca gaaacgccta agcctagttg tggggatcca 1200 gctgcaagaa aaacgttagt ctcttggcct gagcctgcat ctaaacctga tcctgcatct 1260 aaaccccatg gatatgtttt atgctataag aacaattcag aaaaatgtaa aagtttgcct 1320 aataatgtga ccagttttga ggtggaaagc ttgaaacctt ataaatacta tgaagtgtcc 1380 ctacttgcct atgtcaatgg gaagattcaa agaaatggga ctgctgagaa gtgcaatttt 1440 cacacaaaag cagatcgtcc agacaaggtc actggaatga aaacctcccg gccgacagac 1500 aatagtataa atgttacatg tggtcctcct tatgaaacta atggccctaa aaccttttac 1560 attttggtag tcagaagtgg aggttctttt gttacaaaat acaacaagac aaactgtcag 1620 ttttatgtag ataatctcta ctattcaact gactatgagt ttctggtctc ttttcacaat 1680 ggagtgtacg agggagattc agttataaga aatgagtcaa caaattttaa tgctaaagca 1740 ctgattatat tcctggtgtt tctgattatt gtgacatcaa tagccttgct tgttgttttg 1800 tataaaatct atgatctgcg caagaaaaga tccagcaatt tagatgaaca acaggaactc 1860 gttgaaaggg atgatgaaaa gcagctgatg gatgtggagc caatccattc tgacattttg 1920 ttggaaacat acaaaaggaa gattgctgat gagggcagac tgttcctggc tgaatttcag 1980 agcattccac gggtattcag caagtttccc atcaaagatg cccgaaagcc ccacaatcag 2040 aataaaaacc gttatgttga cattcttccc tatgattata accgtgtgga actctctgaa 2100 ataaatggag atgcagggtc cacctacata aatgccagct acattgatgg cttcaaggaa 2160 cccaggaaat acattgctgc acaagggccc cgggatgaga cagttgatga cttctggagg 2220 atgatctggg agcaaaaggc cacagttatt gtcatggtca cacgatgtga agaaggaaac 2280 aggaacaagt gcgcagaata ctggccaagc atggaggaag gcactcgagc tttcaaagat 2340 attgttgtga caatcaatga ccacaaacga tgtcctgatt acatcattca gaagctgaac 2400 gttgcacata aaaaagaaaa agcaactgga agagaagtga ctcatatcca attcaccagc 2460 tggccagacc atggggttcc tgaagaccct cacctgctcc tcaaacttcg acggagagtt 2520 aatgctttta gcaacttctt cagtggtccc attgtggtgc actgcagtgc tggtgttggg 2580 cgtacaggca cctacattgg aattgatgcc atgctggaag gcctggaagc agagggcaaa 2640 gtggatgtct atggttatgt tgtcaagcta aggcgacaga ggtgtctgat ggtgcaagtg 2700 gaggcacagt atatcctgat tcatcaggct ttagtggaat acaatcagtt tggagaaaca 2760 gaagtgaact tgtctgagtt acattcatgc ctacacaaca tgaagaagag agatccaccc 2820 agtgacccct cccctctgga ggctgaatac cagagacttc cttcatacag gagttggagg 2880 acacagcaca ttggaaatca agaagaaaat aagaagaaga acaggaattc taatgttgtt 2940 ccatatgact ttaacagagt gccacttaag catgaactgg agatgagcaa agagagtgag 3000 cctgaatcag atgagtcttc agatgatgac agtgactcag aagaaaccag caaatacatt 3060 aatgcatcct ttgtgatgag ttactggaaa ccagaaatga tgattgctgc tcaggggcca 3120 ctaaaagaaa cgatcggtga cttttggcag atgatattcc aaagaaaagt caaagttatt 3180 gtgatgttga cagagttagt gaatggagac caggaagtct gtgctcagta ctggggcgaa 3240 ggaaagcaga cttatggaga catggaagtg gagatgaaag acacaaacag agcctcagcc 3300 tacactctcc gaacttttga gctgagacat tccaagagga aggagcccag aactgtgtac 3360 cagtaccagt gtaccacatg gaaaggggaa gagctgcctg cagaacccaa agacctggtg 3420 tctatgattc aggacctcaa acagaagctt cccaaggctt ccccagaagg gatgaagtat 3480 cacaagcatg catccatcct cgtccactgc agagatggat cccagcagac agggttgttc 3540 tgtgccttgt tcaatctctt ggaaagtgca gaaacagaag atgtggttga tgttttccaa 3600 gtggtaaagt ctctacgcaa agcacggcct ggggtggtgt gcagctatga gcaataccag 3660 ttcctctatg acatcatcgc cagcatctat cccgcccaga atggacaagt caagaaaaca 3720 aacagccaag acaaaattga atttcataat gaagtggatg gaggcaagca ggatgctaac 3780 tgtgtccgtc cagatggtcc tctgaataaa gcccaggaag acagcagagg ggtgggaacc 3840 ccggagccta ccaatagtgc tgaggaacca gaacatgctg ccaatggttc tgcgagccca 3900 gctccaaccc agagttcata ggaaaggagt catgtgggac aacgcagact ctcacattag 3960 ttctttctat ttttctagac ctaatgaaag aaaatggctg tgcagtggtt tatggaatct 4020 gtgttcacct ttgccactgt ataaaaatat ttaagtttgt caaaacattt tgtacagttt 4080 tatgcttatt ttaaaagtgt atctatgtca ttcagcagga atgtatatgt gagagagggt 4140 gtctgtgtgt gtgagagtgt gtttatgtat gagtgactgt gtgtgtgcat gtttgtgcgt 4200 gtgtatgaca tctaaatgtg attggagaat actttcaagc catttcaaat gctttcgaga 4260 aacagtgtgc cttttctcct cttgaggaaa ctatacattt tatatctaaa ctgttaattt 4320 gtttgaggga ttaatttttt aaaatcccat tgaaagtgga ttcagttgta agaataacaa 4380 tgtgtaccat tctggaatga cctcaaggtg tcctccttgt cctgttgatg atcttgtagt 4440 ttaagatgct ctttttggat atagataagc gtatgtaaga gtgctgtggg tgtgtacagc 4500 tgatctggga cgtgaacaaa atcaacatgt gagacttatg ttccatatac tgtcatttca 4560 tcactatctc ttaatgcata tttaatcaaa catgaaaatc tcaagggaga ctatttttgt 4620 atccacatgg gaagtagaac attgcaagtc agttgctgtc tacacaatag ataaaaatta 4680 ctagttaatg ctcttggtca tatcgatata tgctatgaac ctaaataatt gcccttagcc 4740 aaatataatg tatgttaaaa acacatagaa taaaaacagg ggcatgaaaa cttgtttgta 4800 ctgaatattt acataggtaa cctcgtacag ttagttctgt tatggaattc accatttatg 4860 ggaaatgtaa aattgactat ggccatttcc tatgcttaag accatctttg acttgcatta 4920 ctgtgtattt atcttgaatt tccccactgt tttgtttact cttactgaga tataatattg 4980 ataaccataa taaactttca actatta 5007 <210> SEQ ID NO 83 <211> LENGTH: 1291 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 83 Met Gly Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Leu Leu Asp 1 5 10 15 Thr Glu Val Phe Val Thr Gly Gln Thr Pro Thr Pro Ser Asp Glu Leu 20 25 30 Ser Thr Thr Glu Asn Ala Leu Leu Leu Pro Gln Ser Asp Pro Leu Pro 35 40 45 Ala Arg Thr Thr Glu Ser Thr Pro Pro Ser Ile Ser Glu Arg Gly Asn 50 55 60 Gly Ser Ser Glu Thr Thr Tyr His Pro Gly Val Leu Ser Thr Leu Leu 65 70 75 80 Pro His Leu Ser Pro Gln Pro Asp Ser Gln Thr Pro Ser Ala Gly Gly 85 90 95 Ala Asp Thr Gln Thr Phe Ser Ser Gln Ala Asp Asn Pro Thr Leu Thr 100 105 110 Pro Ala Pro Gly Gly Gly Thr Asp Pro Pro Gly Val Pro Gly Glu Arg 115 120 125 Thr Val Pro Gly Thr Ile Pro Ala Asp Thr Ala Phe Pro Val Asp Thr 130 135 140 Pro Ser Leu Ala Arg Asn Ser Ser Ala Ala Ser Pro Thr His Thr Ser 145 150 155 160 Asn Val Ser Thr Thr Asp Ile Ser Ser Gly Ala Ser Leu Thr Thr Leu 165 170 175 Thr Pro Ser Thr Leu Gly Leu Ala Ser Thr Asp Pro Pro Ser Thr Thr 180 185 190 Ile Ala Thr Thr Thr Lys Gln Thr Cys Ala Ala Met Phe Gly Asn Ile 195 200 205 Thr Val Asn Tyr Thr Tyr Glu Ser Ser Asn Gln Thr Phe Lys Ala Asp 210 215 220 Leu Lys Asp Val Gln Asn Ala Lys Cys Gly Asn Glu Asp Cys Glu Asn 225 230 235 240 Val Leu Asn Asn Leu Glu Glu Cys Ser Gln Ile Lys Asn Ile Ser Val 245 250 255 Ser Asn Asp Ser Cys Ala Pro Ala Thr Thr Ile Asp Leu Tyr Val Pro 260 265 270 Pro Gly Thr Asp Lys Phe Ser Leu His Asp Cys Thr Pro Lys Glu Lys 275 280 285 Ala Asn Thr Ser Ile Cys Leu Glu Trp Lys Thr Glu Asn Leu Asp Phe 290 295 300 Arg Lys Cys Asn Ser Asp Asn Ile Ser Tyr Val Leu His Cys Glu Pro 305 310 315 320 Glu Asn Asn Thr Lys Cys Ile Arg Arg Asn Thr Phe Ile Pro Glu Arg 325 330 335 Cys Gln Leu Asp Asn Leu Arg Ala Gln Thr Asn Tyr Thr Cys Val Ala 340 345 350 Glu Ile Leu Tyr Arg Gly Val Lys Leu Val Lys Asn Val Ile Asn Val 355 360 365 Gln Thr Asp Leu Gly Ile Pro Glu Thr Pro Lys Pro Ser Cys Gly Asp 370 375 380 Pro Ala Ala Arg Lys Thr Leu Val Ser Trp Pro Glu Pro Ala Ser Lys 385 390 395 400 Pro Asp Pro Ala Ser Lys Pro His Gly Tyr Val Leu Cys Tyr Lys Asn 405 410 415 Asn Ser Glu Lys Cys Lys Ser Leu Pro Asn Asn Val Thr Ser Phe Glu 420 425 430 Val Glu Ser Leu Lys Pro Tyr Lys Tyr Tyr Glu Val Ser Leu Leu Ala 435 440 445 Tyr Val Asn Gly Lys Ile Gln Arg Asn Gly Thr Ala Glu Lys Cys Asn 450 455 460 Phe His Thr Lys Ala Asp Arg Pro Asp Lys Val Thr Gly Met Lys Thr 465 470 475 480 Ser Arg Pro Thr Asp Asn Ser Ile Asn Val Thr Cys Gly Pro Pro Tyr 485 490 495 Glu Thr Asn Gly Pro Lys Thr Phe Tyr Ile Leu Val Val Arg Ser Gly 500 505 510 Gly Ser Phe Val Thr Lys Tyr Asn Lys Thr Asn Cys Gln Phe Tyr Val 515 520 525 Asp Asn Leu Tyr Tyr Ser Thr Asp Tyr Glu Phe Leu Val Ser Phe His 530 535 540 Asn Gly Val Tyr Glu Gly Asp Ser Val Ile Arg Asn Glu Ser Thr Asn 545 550 555 560 Phe Asn Ala Lys Ala Leu Ile Ile Phe Leu Val Phe Leu Ile Ile Val 565 570 575 Thr Ser Ile Ala Leu Leu Val Val Leu Tyr Lys Ile Tyr Asp Leu Arg 580 585 590 Lys Lys Arg Ser Ser Asn Leu Asp Glu Gln Gln Glu Leu Val Glu Arg 595 600 605 Asp Asp Glu Lys Gln Leu Met Asp Val Glu Pro Ile His Ser Asp Ile 610 615 620 Leu Leu Glu Thr Tyr Lys Arg Lys Ile Ala Asp Glu Gly Arg Leu Phe 625 630 635 640 Leu Ala Glu Phe Gln Ser Ile Pro Arg Val Phe Ser Lys Phe Pro Ile 645 650 655 Lys Asp Ala Arg Lys Pro His Asn Gln Asn Lys Asn Arg Tyr Val Asp 660 665 670 Ile Leu Pro Tyr Asp Tyr Asn Arg Val Glu Leu Ser Glu Ile Asn Gly 675 680 685 Asp Ala Gly Ser Thr Tyr Ile Asn Ala Ser Tyr Ile Asp Gly Phe Lys 690 695 700 Glu Pro Arg Lys Tyr Ile Ala Ala Gln Gly Pro Arg Asp Glu Thr Val 705 710 715 720 Asp Asp Phe Trp Arg Met Ile Trp Glu Gln Lys Ala Thr Val Ile Val 725 730 735 Met Val Thr Arg Cys Glu Glu Gly Asn Arg Asn Lys Cys Ala Glu Tyr 740 745 750 Trp Pro Ser Met Glu Glu Gly Thr Arg Ala Phe Lys Asp Ile Val Val 755 760 765 Thr Ile Asn Asp His Lys Arg Cys Pro Asp Tyr Ile Ile Gln Lys Leu 770 775 780 Asn Val Ala His Lys Lys Glu Lys Ala Thr Gly Arg Glu Val Thr His 785 790 795 800 Ile Gln Phe Thr Ser Trp Pro Asp His Gly Val Pro Glu Asp Pro His 805 810 815 Leu Leu Leu Lys Leu Arg Arg Arg Val Asn Ala Phe Ser Asn Phe Phe 820 825 830 Ser Gly Pro Ile Val Val His Cys Ser Ala Gly Val Gly Arg Thr Gly 835 840 845 Thr Tyr Ile Gly Ile Asp Ala Met Leu Glu Gly Leu Glu Ala Glu Gly 850 855 860 Lys Val Asp Val Tyr Gly Tyr Val Val Lys Leu Arg Arg Gln Arg Cys 865 870 875 880 Leu Met Val Gln Val Glu Ala Gln Tyr Ile Leu Ile His Gln Ala Leu 885 890 895 Val Glu Tyr Asn Gln Phe Gly Glu Thr Glu Val Asn Leu Ser Glu Leu 900 905 910 His Ser Cys Leu His Asn Met Lys Lys Arg Asp Pro Pro Ser Asp Pro 915 920 925 Ser Pro Leu Glu Ala Glu Tyr Gln Arg Leu Pro Ser Tyr Arg Ser Trp 930 935 940 Arg Thr Gln His Ile Gly Asn Gln Glu Glu Asn Lys Lys Lys Asn Arg 945 950 955 960 Asn Ser Asn Val Val Pro Tyr Asp Phe Asn Arg Val Pro Leu Lys His 965 970 975 Glu Leu Glu Met Ser Lys Glu Ser Glu Pro Glu Ser Asp Glu Ser Ser 980 985 990 Asp Asp Asp Ser Asp Ser Glu Glu Thr Ser Lys Tyr Ile Asn Ala Ser 995 1000 1005 Phe Val Met Ser Tyr Trp Lys Pro Glu Met Met Ile Ala Ala Gln Gly 1010 1015 1020 Pro Leu Lys Glu Thr Ile Gly Asp Phe Trp Gln Met Ile Phe Gln Arg 1025 1030 1035 1040 Lys Val Lys Val Ile Val Met Leu Thr Glu Leu Val Asn Gly Asp Gln 1045 1050 1055 Glu Val Cys Ala Gln Tyr Trp Gly Glu Gly Lys Gln Thr Tyr Gly Asp 1060 1065 1070 Met Glu Val Glu Met Lys Asp Thr Asn Arg Ala Ser Ala Tyr Thr Leu 1075 1080 1085 Arg Thr Phe Glu Leu Arg His Ser Lys Arg Lys Glu Pro Arg Thr Val 1090 1095 1100 Tyr Gln Tyr Gln Cys Thr Thr Trp Lys Gly Glu Glu Leu Pro Ala Glu 1105 1110 1115 1120 Pro Lys Asp Leu Val Ser Met Ile Gln Asp Leu Lys Gln Lys Leu Pro 1125 1130 1135 Lys Ala Ser Pro Glu Gly Met Lys Tyr His Lys His Ala Ser Ile Leu 1140 1145 1150 Val His Cys Arg Asp Gly Ser Gln Gln Thr Gly Leu Phe Cys Ala Leu 1155 1160 1165 Phe Asn Leu Leu Glu Ser Ala Glu Thr Glu Asp Val Val Asp Val Phe 1170 1175 1180 Gln Val Val Lys Ser Leu Arg Lys Ala Arg Pro Gly Val Val Cys Ser 1185 1190 1195 1200 Tyr Glu Gln Tyr Gln Phe Leu Tyr Asp Ile Ile Ala Ser Ile Tyr Pro 1205 1210 1215 Ala Gln Asn Gly Gln Val Lys Lys Thr Asn Ser Gln Asp Lys Ile Glu 1220 1225 1230 Phe His Asn Glu Val Asp Gly Gly Lys Gln Asp Ala Asn Cys Val Arg 1235 1240 1245 Pro Asp Gly Pro Leu Asn Lys Ala Gln Glu Asp Ser Arg Gly Val Gly 1250 1255 1260 Thr Pro Glu Pro Thr Asn Ser Ala Glu Glu Pro Glu His Ala Ala Asn 1265 1270 1275 1280 Gly Ser Ala Ser Pro Ala Pro Thr Gln Ser Ser 1285 1290 <210> SEQ ID NO 84 <211> LENGTH: 3541 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 84 tgggtgggtg tctcaaaaaa caaaaaactc agaagataca aatggagaaa aaaaatctaa 60 acaccccaaa agaaacccaa ggatgacagt agtaagaatt ttaacgcaaa cctagaaggt 120 gacaaaaaac ctaagtgtga atatacggat tgtgaaaaag agttaaaaaa tctaccagaa 180 tgctcacaga aaaacgtcac tctctccaat ggctcatgta ctccagataa aattataaat 240 ttagatgtac caccagggac tcacaacttt aacttaacaa actgcacacc agacatagaa 300 gctaatacct caatttgttt ggagtggaaa ataaaaaaca aatttacctg cgacattcaa 360 aagatttcat acaatttccg ttgtacacca gagatgaaaa catttgcttt ggacaaacac 420 ggaacacttt ggttacacaa ccttacagtc cgaacaaatt acacatgtgc tgcggaagtc 480 ctctacaata acgtaatact tttaaaacaa gacagaaggg tgcagactga ttttgggact 540 ccagaaatgc ttccccatgt tcaatgtaag aattcaacta acagcacaac attagtctcc 600 tgggctgagc cagcatctaa acaccatgga tacattttat gctataaaaa gaccccttca 660 gaaaaatgtg aaaatttggc taatgatgtg aacagttttg aggtgaaaaa cctgaggcct 720 tatacagagt acacagtgtc tctatttgcc tatgttattg ggagggtgca acgaaatggc 780 cctgctaagg attgcaactt tcggacaaaa gcagctcgtc caggcaaagt caatggtatg 840 aaaacctccc gggcgtcaga caatagtata aatgtcacgt gtaattctcc ttatgaaatt 900 aatggccctg aagcgcgtta cattttggaa gtcaaaagtg gaggttcttt agttaaaact 960 ttcaaccaat ccacatgtaa atttgttgta gacaatctct attattcaac tgactatgag 1020 tttctggtct atttttacaa tggagagtac ctgggagacc cagaaataaa acctcaatca 1080 acatcttata attctaaagc actgattata ttcctggtgt ttctgattat tgtgacatca 1140 atagccctgc ttgttgtttt gtataaaatc tatgatctgc gtaagaaaag atccagcaat 1200 ttagatgaac agcaggaact cgttgaaagg gatgaggaga agcagctgat aaatgtggac 1260 ccaattcatt ctgacctttt gttggaaaca tacaaaagaa agattgccga tgagggtaga 1320 ctgttcctgg ctgaatttca gagcattcca cgggtattca gcaagtttcc catcaaagat 1380 gcccgaaagt cccaaaacca gaacaaaaac cgttatgtgg acattctccc ctatgattac 1440 aaccgtgtgg agctctctga aataaatgga gacgcagggt ccacctacat aaatgccagc 1500 tacattgatg gcttcaagga acccaggaaa tacattgctg cacaagggcc ccgggatgag 1560 acagttgatg acttctggaa gatgatctgg gagcagaagg ccacagttat tgtcatggtc 1620 acacgatgtg aagaaggaaa caggaacaag tgtgcagaat attggccatg catggaggaa 1680 ggcactcgga ctttcagaga tgttgtcgtg acgatcaatg accacaaacg atgtcctgat 1740 tacattatcc agaagctgag cattgcccac aaaaaagaaa aagcaactgg aagagaagtg 1800 actcatattc aattcaccag ttggccagac catggggttc ctgaagaccc tcacctgctc 1860 ctgaaacttc gacggagagt taatgctttt agcaacttct tcagtggacc cattgtggtg 1920 cactgcagtg ctggcgttgg gcgtacaggc acctacattg gaattgatgc catgctcgaa 1980 agcctagaag cagagggcaa agtggatgtc tatggctatg ttgtcaacct aaggcgacag 2040 agatgtctga tggtgcaagt ggaggcccag tacatcctga tccatcaggc cttagtggag 2100 tacaatcaat ttggggaaac agaagtgaac ttgtctgagt tacattcatg tctacagaat 2160 ctgaagaaga gagatccacc cagtgacccg tctcctttgg aggctgagta ccagagactt 2220 ccttcataca ggagctggag gacacagcac attggaaatc aagaagaaaa taaaaagaaa 2280 aacaggagtt ctaacgttgt tccatatgac tttaacagag tgccacttaa gcatgaacta 2340 gagatgagca aagagagcga ggctgaatcc gacgaatctt cagatgagga cagtgactcg 2400 gaagaaacca gcaaatacat taatgcgtca tttgtgatga gttactggaa accagaaatg 2460 atgattgctg cccagggtcc actaaaagag actattggtg acttttggca gatgatattc 2520 caaagaaaag tcaaggttat tgtgatgttg acagagttaa tgagtggaga ccaggaagtc 2580 tgtgctcaat actggggaga aggaaagcag acttatggag acatggaagt aatgttgaaa 2640 gacacgaaca aatcctcagc ctatattctg cgagcatttg aactgagaca ttccaagaga 2700 aaggagccta gaactgtgta ccagtaccag tgtaccacat ggaaagggga ggagctccct 2760 gcagaaccca aagatctggt gactctgatt cagaacatca aacagaagct tcccaagagt 2820 ggctcagaag ggatgaagta ccacaagcat gcatcaatcc tagtccactg cagggatgga 2880 tcccagcaga cggggttgtt ctgtgctctg ttcaatctcc tggaaagtgc agaaacagaa 2940 gatgtggttg atgtttttca agtggtaaag tctctacgca aagcacggcc ggggatggtg 3000 ggcagctttg agcaatacca gttcctctat gacatcatgg ccagcatcta tcccacccag 3060 aatggacaag tgaagaaagc aaacagccaa gacaaaattg aatttcataa cgaagtggac 3120 ggagccaagc aggacgcaaa ctgtgttcag ccagctgatc ctctgaacaa agcccaggaa 3180 gacagcaaag aagttggagc ttcagagcct gcaagtggtt ctgaggagcc agaacattct 3240 gcaaatggtc ccatgagccc agctctaacc ccgagctcat aggaacggat tcgagtggga 3300 caacgcaaaa tgtcaaatta gttgtttcta tttttctaga cctaatgaaa aaatatggct 3360 gtacagtggt ccgtggaatc tgtgttcacc tttgccactg tataaaaata tttaagtttg 3420 tcaaaaggtt ttgtacagtt ttatgcctat tttaaaaatg tatctatatc atttagcaag 3480 agtgtgtgta ggagagtatg tctgtgtgtg agagagtgtg tgcttctgtt agtgtgtgtt 3540 t 3541 <210> SEQ ID NO 85 <211> LENGTH: 962 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 85 Met Lys Thr Phe Ala Leu Asp Lys His Gly Thr Leu Trp Leu His Asn 1 5 10 15 Leu Thr Val Arg Thr Asn Tyr Thr Cys Ala Ala Glu Val Leu Tyr Asn 20 25 30 Asn Val Ile Leu Leu Lys Gln Asp Arg Arg Val Gln Thr Asp Phe Gly 35 40 45 Thr Pro Glu Met Leu Pro His Val Gln Cys Lys Asn Ser Thr Asn Ser 50 55 60 Thr Thr Leu Val Ser Trp Ala Glu Pro Ala Ser Lys His His Gly Tyr 65 70 75 80 Ile Leu Cys Tyr Lys Lys Thr Pro Ser Glu Lys Cys Glu Asn Leu Ala 85 90 95 Asn Asp Val Asn Ser Phe Glu Val Lys Asn Leu Arg Pro Tyr Thr Glu 100 105 110 Tyr Thr Val Ser Leu Phe Ala Tyr Val Ile Gly Arg Val Gln Arg Asn 115 120 125 Gly Pro Ala Lys Asp Cys Asn Phe Arg Thr Lys Ala Ala Arg Pro Gly 130 135 140 Lys Val Asn Gly Met Lys Thr Ser Arg Ala Ser Asp Asn Ser Ile Asn 145 150 155 160 Val Thr Cys Asn Ser Pro Tyr Glu Ile Asn Gly Pro Glu Ala Arg Tyr 165 170 175 Ile Leu Glu Val Lys Ser Gly Gly Ser Leu Val Lys Thr Phe Asn Gln 180 185 190 Ser Thr Cys Lys Phe Val Val Asp Asn Leu Tyr Tyr Ser Thr Asp Tyr 195 200 205 Glu Phe Leu Val Tyr Phe Tyr Asn Gly Glu Tyr Leu Gly Asp Pro Glu 210 215 220 Ile Lys Pro Gln Ser Thr Ser Tyr Asn Ser Lys Ala Leu Ile Ile Phe 225 230 235 240 Leu Val Phe Leu Ile Ile Val Thr Ser Ile Ala Leu Leu Val Val Leu 245 250 255 Tyr Lys Ile Tyr Asp Leu Arg Lys Lys Arg Ser Ser Asn Leu Asp Glu 260 265 270 Gln Gln Glu Leu Val Glu Arg Asp Glu Glu Lys Gln Leu Ile Asn Val 275 280 285 Asp Pro Ile His Ser Asp Leu Leu Leu Glu Thr Tyr Lys Arg Lys Ile 290 295 300 Ala Asp Glu Gly Arg Leu Phe Leu Ala Glu Phe Gln Ser Ile Pro Arg 305 310 315 320 Val Phe Ser Lys Phe Pro Ile Lys Asp Ala Arg Lys Ser Gln Asn Gln 325 330 335 Asn Lys Asn Arg Tyr Val Asp Ile Leu Pro Tyr Asp Tyr Asn Arg Val 340 345 350 Glu Leu Ser Glu Ile Asn Gly Asp Ala Gly Ser Thr Tyr Ile Asn Ala 355 360 365 Ser Tyr Ile Asp Gly Phe Lys Glu Pro Arg Lys Tyr Ile Ala Ala Gln 370 375 380 Gly Pro Arg Asp Glu Thr Val Asp Asp Phe Trp Lys Met Ile Trp Glu 385 390 395 400 Gln Lys Ala Thr Val Ile Val Met Val Thr Arg Cys Glu Glu Gly Asn 405 410 415 Arg Asn Lys Cys Ala Glu Tyr Trp Pro Cys Met Glu Glu Gly Thr Arg 420 425 430 Thr Phe Arg Asp Val Val Val Thr Ile Asn Asp His Lys Arg Cys Pro 435 440 445 Asp Tyr Ile Ile Gln Lys Leu Ser Ile Ala His Lys Lys Glu Lys Ala 450 455 460 Thr Gly Arg Glu Val Thr His Ile Gln Phe Thr Ser Trp Pro Asp His 465 470 475 480 Gly Val Pro Glu Asp Pro His Leu Leu Leu Lys Leu Arg Arg Arg Val 485 490 495 Asn Ala Phe Ser Asn Phe Phe Ser Gly Pro Ile Val Val His Cys Ser 500 505 510 Ala Gly Val Gly Arg Thr Gly Thr Tyr Ile Gly Ile Asp Ala Met Leu 515 520 525 Glu Ser Leu Glu Ala Glu Gly Lys Val Asp Val Tyr Gly Tyr Val Val 530 535 540 Asn Leu Arg Arg Gln Arg Cys Leu Met Val Gln Val Glu Ala Gln Tyr 545 550 555 560 Ile Leu Ile His Gln Ala Leu Val Glu Tyr Asn Gln Phe Gly Glu Thr 565 570 575 Glu Val Asn Leu Ser Glu Leu His Ser Cys Leu Gln Asn Leu Lys Lys 580 585 590 Arg Asp Pro Pro Ser Asp Pro Ser Pro Leu Glu Ala Glu Tyr Gln Arg 595 600 605 Leu Pro Ser Tyr Arg Ser Trp Arg Thr Gln His Ile Gly Asn Gln Glu 610 615 620 Glu Asn Lys Lys Lys Asn Arg Ser Ser Asn Val Val Pro Tyr Asp Phe 625 630 635 640 Asn Arg Val Pro Leu Lys His Glu Leu Glu Met Ser Lys Glu Ser Glu 645 650 655 Ala Glu Ser Asp Glu Ser Ser Asp Glu Asp Ser Asp Ser Glu Glu Thr 660 665 670 Ser Lys Tyr Ile Asn Ala Ser Phe Val Met Ser Tyr Trp Lys Pro Glu 675 680 685 Met Met Ile Ala Ala Gln Gly Pro Leu Lys Glu Thr Ile Gly Asp Phe 690 695 700 Trp Gln Met Ile Phe Gln Arg Lys Val Lys Val Ile Val Met Leu Thr 705 710 715 720 Glu Leu Met Ser Gly Asp Gln Glu Val Cys Ala Gln Tyr Trp Gly Glu 725 730 735 Gly Lys Gln Thr Tyr Gly Asp Met Glu Val Met Leu Lys Asp Thr Asn 740 745 750 Lys Ser Ser Ala Tyr Ile Leu Arg Ala Phe Glu Leu Arg His Ser Lys 755 760 765 Arg Lys Glu Pro Arg Thr Val Tyr Gln Tyr Gln Cys Thr Thr Trp Lys 770 775 780 Gly Glu Glu Leu Pro Ala Glu Pro Lys Asp Leu Val Thr Leu Ile Gln 785 790 795 800 Asn Ile Lys Gln Lys Leu Pro Lys Ser Gly Ser Glu Gly Met Lys Tyr 805 810 815 His Lys His Ala Ser Ile Leu Val His Cys Arg Asp Gly Ser Gln Gln 820 825 830 Thr Gly Leu Phe Cys Ala Leu Phe Asn Leu Leu Glu Ser Ala Glu Thr 835 840 845 Glu Asp Val Val Asp Val Phe Gln Val Val Lys Ser Leu Arg Lys Ala 850 855 860 Arg Pro Gly Met Val Gly Ser Phe Glu Gln Tyr Gln Phe Leu Tyr Asp 865 870 875 880 Ile Met Ala Ser Ile Tyr Pro Thr Gln Asn Gly Gln Val Lys Lys Ala 885 890 895 Asn Ser Gln Asp Lys Ile Glu Phe His Asn Glu Val Asp Gly Ala Lys 900 905 910 Gln Asp Ala Asn Cys Val Gln Pro Ala Asp Pro Leu Asn Lys Ala Gln 915 920 925 Glu Asp Ser Lys Glu Val Gly Ala Ser Glu Pro Ala Ser Gly Ser Glu 930 935 940 Glu Pro Glu His Ser Ala Asn Gly Pro Met Ser Pro Ala Leu Thr Pro 945 950 955 960 Ser Ser <210> SEQ ID NO 86 <211> LENGTH: 2090 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 2090 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 86 cttagtccct gagctctctg cctgcccaga ctagctgcac ctcctcattc cctgcgcccc 60 cttcctctcc ggaagccccc aggatggtga ggtggtttca ccgagacctc agtgggctgg 120 atgcagagac cctgctcaag ggccgaggtg tccacggtag cttcctggct cggcccagtc 180 gcaagaacca gggtgacttc tcgctctccg tcagggtggg ggatcaggtg acccatattc 240 ggatccagaa ctcaggggat ttctatgacc tgtatggagg ggagaagttt gcgactctga 300 cagagctggt ggagtactac actcagcagc agggtgtcct gcaggaccgc gacggcacca 360 tcatccacct caagtacccg ctgaactgct ccgatcccac tagtgagagg tggtaccatg 420 gccacatgtc tggcgggcag gcagagacgc tgctgcaggc caagggcgag ccctggacgt 480 ttcttgtgcg tgagagcctc agccagcctg gagacttcgt gctttctgtg ctcagtgacc 540 agcccaaggc tggcccaggc tccccgctca gggtcaccca catcaaggtc atgtgcgagg 600 gtggacgcta cacagtgggt ggtttggaga ccttcgacag cctcacggac ctggtggagc 660 atttcaagaa gacggggatt gaggaggcct caggcgcctt tgtctacctg cggcagccgt 720 actatgccac gagggtgaat gcggctgaca ttgagaaccg agtgttggaa ctgaacaaga 780 agcaggagtc cgaggataca gccaaggctg gcttctggga ggagtttgag agtttgcaga 840 agcaggaggt gaagaacttg caccagcgtc tggaagggca gcggccagag aacaagggca 900 agaaccgcta caagaacatt ctcccctttg accacagccg agtgatcctg cagggacggg 960 acagtaacat ccccgggtcc gactacatca atgccaacta catcaagaac cagctgctag 1020 gccctgatga gaacgctaag acctacatcg ccagccaggg ctgtctggag gccacggtca 1080 atgacttctg gcagatggcg tggcaggaga acagccgtgt catcgtcatg accacccgag 1140 aggtggagaa aggccggaac aaatgcgtcc catactggcc cgaggtgggc atgcagcgtg 1200 cttatgggcc ctactctgtg accaactgcg gggagcatga cacaaccgaa tacaaactcc 1260 gtaccttaca ggtctccccg ctggacaatg gagacctgat tcgggagatc tggcattacc 1320 agtacctgag ctggcccgac catggggtcc ccagtgagcc tgggggtgtc ctcagcttcc 1380 tggaccagat caaccagcgg caggaaagtc tgcctcacgc agggcccatc atcgtgcact 1440 gcagcgccgg catcggccgc acaggcacca tcattgtcat cgacatgctc atggagaaca 1500 tctccaccaa gggcctggac tgtgacattg acatccagaa gaccatccag atggtgcggg 1560 cgcagcgctc gggcatggtg cagacggagg cgcagtacaa gttcatctac gtggccatcg 1620 cccagttcat tgaaaccact aagaagaagc tggaggtcct gcagtcgcag aagggccagg 1680 agtcggagta cgggaacatc acctatcccc cagccatgaa gaatgcccat gccaaggcct 1740 cccgcacctc gtccaaacac aaggaggatg tgtatgagaa cctgcacact aagaacaaga 1800 gggaggagaa agtgaagaag cagcggtcag cagacaagga gaagagcaag ggttccctca 1860 agaggaagtg agcggtgctg tcctcaggtg gccatgcctc agccctgacc ctgtggaagg 1920 atttcgcgat ggacagactc acaacctgaa cctaggagat gtcgtattct tttgtaattt 1980 aaatggctgt atcccccccc taacctctcc ctgaccctgt atatagccca gccaggccca 2040 gcagggccac ccttctcctc ttgtaaataa agccctggga tcactgtgan 2090 <210> SEQ ID NO 87 <211> LENGTH: 595 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 87 Met Val Arg Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr 1 5 10 15 Leu Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser 20 25 30 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln 35 40 45 Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr 50 55 60 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr 65 70 75 80 Gln Gln Gln Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile His Leu 85 90 95 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp Tyr His 100 105 110 Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly 115 120 125 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro Gly Asp 130 135 140 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser 145 150 155 160 Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly Arg Tyr 165 170 175 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu Val Glu 180 185 190 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr 195 200 205 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val Asn Ala Ala Asp Ile Glu 210 215 220 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Glu Ser Glu Asp Thr Ala 225 230 235 240 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Leu Gln Lys Gln Glu Val 245 250 255 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Arg Pro Glu Asn Lys Gly 260 265 270 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Ser Arg Val Ile 275 280 285 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Ser Asp Tyr Ile Asn Ala 290 295 300 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro Asp Glu Asn Ala Lys Thr 305 310 315 320 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Thr Val Asn Asp Phe Trp 325 330 335 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Ile Val Met Thr Thr Arg 340 345 350 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pro Tyr Trp Pro Glu Val 355 360 365 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Val Thr Asn Cys Gly Glu 370 375 380 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Leu Gln Val Ser Pro Leu 385 390 395 400 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp His Tyr Gln Tyr Leu Ser 405 410 415 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gly Gly Val Leu Ser Phe 420 425 430 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Leu Pro His Ala Gly Pro 435 440 445 Ile Ile Val His Cys Ser Ala Gly Ile Gly Arg Thr Gly Thr Ile Ile 450 455 460 Val Ile Asp Met Leu Met Glu Asn Ile Ser Thr Lys Gly Leu Asp Cys 465 470 475 480 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Val Arg Ala Gln Arg Ser 485 490 495 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Phe Ile Tyr Val Ala Ile 500 505 510 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Leu Glu Val Leu Gln Ser 515 520 525 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Ile Thr Tyr Pro Pro Ala 530 535 540 Met Lys Asn Ala His Ala Lys Ala Ser Arg Thr Ser Ser Lys His Lys 545 550 555 560 Glu Asp Val Tyr Glu Asn Leu His Thr Lys Asn Lys Arg Glu Glu Lys 565 570 575 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Lys Ser Lys Gly Ser Leu 580 585 590 Lys Arg Lys 595 <210> SEQ ID NO 88 <211> LENGTH: 2277 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 88 caagaagacg gggattgagg aggcctcagg cgcctttgtc tacctgcggc agccgtacta 60 tgccacgagg gtgaatgcgg ctgacattga gaaccgagtg ttggaactga acaagaagca 120 ggagtccgag gaggaagtgg ctgattactg agcggttctt cctcacctgg cttgggccac 180 tgtgcacagc tgtgccgctg gctcagcccc gccccctgcg gccctccgcc gtggcttccc 240 cctccctaca gagagatgct gtcccgtggg tggtttcacc gagacctcag tgggctggat 300 gcagagaccc tgctcaaggg ccgaggtgtc cacggtagct tcctggctcg gcccagtcgc 360 aagaaccagg gtgacttctc gctctccgtc agggtggggg atcaggtgac ccatattcgg 420 atccagaact caggggattt ctatgacctg tatggagggg agaagtttgc gactctgaca 480 gagctggtgg agtactacac tcagcagcag ggtgtcctgc aggaccgcga cggcaccatc 540 atccacctca agtacccgct gaactgctcc gatcccacta gtgagaggtg gtaccatggc 600 cacatgtctg gcgggcaggc agagacgctg ctgcaggcca agggcgagcc ctggacgttt 660 cttgtgcgtg agagcctcag ccagcctgga gacttcgtgc tttctgtgct cagtgaccag 720 cccaaggctg gcccaggctc cccgctcagg gtcacccaca tcaaggtcat gtgcgagggt 780 ggacgctaca cagtgggtgg tttggagacc ttcgacagcc tcacggacct ggtagagcat 840 ttcaagaaga cggggattga ggaggcctca ggcgcctttg tctacctgcg gcagccgtac 900 tatgccacga gggtgaatgc ggctgacatt gagaaccgag tgttggaact gaacaagaag 960 caggagtccg aggatacagc caaggctggc ttctgggagg agtttgagag tttgcagaag 1020 caggaggtga agaacttgca ccagcgtctg gaagggcagc ggccagagaa caagggcaag 1080 aaccgctaca agaacattct cccctttgac cacagccgag tgatcctgca gggacgggac 1140 agtaacatcc ccgggtccga ctacatcaat gccaactaca tcaagaacca gctgctaggc 1200 cctgatgaga acgctaagac ctacatcgcc agccagggct gtctggaggc cacggtcaat 1260 gacttctggc agatggcgtg gcaggagaac agccgtgtca tcgtcatgac cacccgagag 1320 gtggagaaag gccggaacaa atgcgtccca tactggcccg aggtgggcat gcagcgtgct 1380 tatgggccct actctgtgac caactgcggg gagcatgaca caaccgaata caaactccgt 1440 accttacagg tctccccgct ggacaatgga gacctgattc gggagatctg gcattaccag 1500 tacctgagct ggcccgacca tggggtcccc agtgagcctg ggggtgtcct cagcttcctg 1560 gaccagatca accagcggca ggaaagtctg cctcacgcag ggcccatcat cgtgcactgc 1620 agcgccggca tcggccgcac aggcaccatc attgtcatcg acatgctcat ggagaacatc 1680 tccaccaagg gcctggactg tgacattgac atccagaaga ccatccagat ggtgcgggcg 1740 cagcgctcgg gcatggtgca gacggaggcg cagtacaagt tcatctacgt ggccatcgcc 1800 cagttcattg aaaccactaa gaagaagctg gaggtcctgc agtcgcagaa gggccaggag 1860 tcggagtacg ggaacatcac ctatccccca gccatgaaga atgcccatgc caaggcctcc 1920 cgcacctcgt ccaaacacaa ggaggatgtg tatgagaacc tgcacactaa gaacaagagg 1980 gaggagaaag tgaagaagca gcggtcagca gacaaggaga agagcaaggg ttccctcaag 2040 aggaagtgag cggtgctgtc ctcaggtggc catgcctcag ccctgaccct gtggaagcat 2100 ttcgcgatgg acagactcac aacctgaacc taggagtgcc ccattctttt gtaatttaaa 2160 tggctgcatc ccccccacct ctccctgacc ctgtatatag cccagccagg ccccaggcag 2220 ggccaaccct tctcctcttg taaataaagc cctgggatca ctgaaaaaaa aaaaaaa 2277 <210> SEQ ID NO 89 <211> LENGTH: 597 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 89 Met Leu Ser Arg Gly Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala 1 5 10 15 Glu Thr Leu Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly 35 40 45 Asp Gln Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr 65 70 75 80 Tyr Thr Gln Gln Gln Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile 85 90 95 His Leu Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp 100 105 110 Tyr His Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala 115 120 125 Lys Gly Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro 145 150 155 160 Gly Ser Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly 165 170 175 Arg Tyr Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu 180 185 190 Val Glu His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe 195 200 205 Val Tyr Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val Asn Ala Ala Asp 210 215 220 Ile Glu Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Glu Ser Glu Asp 225 230 235 240 Thr Ala Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Leu Gln Lys Gln 245 250 255 Glu Val Lys Asn Leu His Gln Arg Leu Glu Gly Gln Arg Pro Glu Asn 260 265 270 Lys Gly Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Ser Arg 275 280 285 Val Ile Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Ser Asp Tyr Ile 290 295 300 Asn Ala Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro Asp Glu Asn Ala 305 310 315 320 Lys Thr Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Thr Val Asn Asp 325 330 335 Phe Trp Gln Met Ala Trp Gln Glu Asn Ser Arg Val Ile Val Met Thr 340 345 350 Thr Arg Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pro Tyr Trp Pro 355 360 365 Glu Val Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Val Thr Asn Cys 370 375 380 Gly Glu His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Leu Gln Val Ser 385 390 395 400 Pro Leu Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp His Tyr Gln Tyr 405 410 415 Leu Ser Trp Pro Asp His Gly Val Pro Ser Glu Pro Gly Gly Val Leu 420 425 430 Ser Phe Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Leu Pro His Ala 435 440 445 Gly Pro Ile Ile Val His Cys Ser Ala Gly Ile Gly Arg Thr Gly Thr 450 455 460 Ile Ile Val Ile Asp Met Leu Met Glu Asn Ile Ser Thr Lys Gly Leu 465 470 475 480 Asp Cys Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Val Arg Ala Gln 485 490 495 Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Phe Ile Tyr Val 500 505 510 Ala Ile Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Leu Glu Val Leu 515 520 525 Gln Ser Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Ile Thr Tyr Pro 530 535 540 Pro Ala Met Lys Asn Ala His Ala Lys Ala Ser Arg Thr Ser Ser Lys 545 550 555 560 His Lys Glu Asp Val Tyr Glu Asn Leu His Thr Lys Asn Lys Arg Glu 565 570 575 Glu Lys Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Lys Ser Lys Gly 580 585 590 Ser Leu Lys Arg Lys 595 <210> SEQ ID NO 90 <211> LENGTH: 2145 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 cggcagaact gggaccaccg ggggtggtga ggcggcccgg cactgggagc tgcatctgag 60 gcttagtccc tgagctctct gcctgcccag actagctgca cctcctcatt ccctgcgccc 120 ccttcctctc cggaagcccc caggatggtg aggtggtttc accgagacct cagtgggctg 180 gatgcagaga ccctgctcaa gggccgaggt gtccacggta gcttcctggc tcggcccagt 240 cgcaagaacc agggtgactt ctcgctctcc gtcagggtgg gggatcaggt gacccatatt 300 cggatccaga actcagggga tttctatgac ctgtatggag gggagaagtt tgcgactctg 360 acagagctgg tggagtacta cactcagcag cagggtgtgg tgcaggaccg cgacggcacc 420 atcatccacc tcaagtaccc gctgaactgc tccgatccca ctagtgagag gtggtaccat 480 ggccacatgt ctggcgggca ggcagagacg ctgctgcagg ccaagggcga gccctggacg 540 tttcttgtgc gtgagagcct cagccagcct ggagacttcg tgctttctgt gctcagtgac 600 cagcccaagg ctggcccagg ctccccgctc agggtcaccc acatcaaggt catgtgcgag 660 ggtggacgct acacagtggg tggtttggag accttcgaca gcctcacgga cctggtggag 720 catttcaaga agacggggat tgaggaggcc tcaggcgcct ttgtctacct gcggcagccg 780 tactatgcca cgagggtgaa tgcggctgac attgagaacc gagtgttgga actgaacaag 840 aagcaggagt ccgaggatac agccaaggct ggcttctggg aggagtttga gagtttgcag 900 aagcaggagg tgaagaactt gcaccagcgt ctggaagggc aacggccaga gaacaagggc 960 aagaaccgct acaagaacat tctccccttt gaccacagcc gagtgatcct gcagggacgg 1020 gacagtaaca tccccgggtc cgactacatc aatgccaact acatcaagaa ccagctgcta 1080 ggccctgatg agaacgctaa gacctacatc gccagccagg gctgtctgga ggccacggtc 1140 aatgacttct ggcagatggc gtggcaggag aacagccgtg tcatcgtcat gaccacccga 1200 gaggtggaga aaggccggaa caaatgcgtc ccatactggc ccgaggtggg catgcagcgt 1260 gcttatgggc cctactctgt gaccaactgc ggggagcatg acacaaccga atacaaactc 1320 cgtaccttac aggtctcccc gctggacaat ggagacctga ttcgggagat ctggcattac 1380 cagtacctga gctggcccga ccatggggtc cccagtgagc ctgggggtgt cctcagcttc 1440 ctggaccaga tcaaccagcg gcaggaaagt ctgcctcacg cagggcccat catcgtgcac 1500 tgcagcgccg gcatcggccg cacaggcacc atcattgtca tcgacatgct catggagaac 1560 atctccacca agggcctgga ctgtgacatt gacatccaga agaccatcca gatggtgcgg 1620 gcgcagcgct cgggcatggt gcagacggag gcgcagtaca agttcatcta cgtggccatc 1680 gcccagttca ttgaaaccac taagaagaag ctggaggtcc tgcagtcgca gaagggccag 1740 gagtcggagt acgggaacat cacctatccc ccagccatga agaatgccca tgccaaggcc 1800 tcccgcacct cgtccaaaca caaggaggat gtgtatgaga acctgcacac taagaacaag 1860 agggaggaga aagtgaagaa gcagcggtca gcagacaagg agaagagcaa gggttccctc 1920 aagaggaagt gagcggtgct gtcctcaggt ggccatgcct cagccctgac cctgtggaag 1980 catttcgcga tggacagact cacaacctga acctaggagt gccccattct tttgtaattt 2040 aaatggctgc atccccccca cctctccctg accctgtata tagcccagcc aggccccagg 2100 cagggccaac ccttctcctc ttgtaaataa agccctggga tcact 2145 <210> SEQ ID NO 91 <211> LENGTH: 595 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 91 Met Val Arg Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr 1 5 10 15 Leu Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser 20 25 30 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln 35 40 45 Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr 50 55 60 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr 65 70 75 80 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gly Thr Ile Ile His Leu 85 90 95 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp Tyr His 100 105 110 Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly 115 120 125 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro Gly Asp 130 135 140 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser 145 150 155 160 Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly Arg Tyr 165 170 175 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu Val Glu 180 185 190 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr 195 200 205 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val Asn Ala Ala Asp Ile Glu 210 215 220 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Glu Ser Glu Asp Thr Ala 225 230 235 240 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Leu Gln Lys Gln Glu Val 245 250 255 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Arg Pro Glu Asn Lys Gly 260 265 270 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Ser Arg Val Ile 275 280 285 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Ser Asp Tyr Ile Asn Ala 290 295 300 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro Asp Glu Asn Ala Lys Thr 305 310 315 320 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Thr Val Asn Asp Phe Trp 325 330 335 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Ile Val Met Thr Thr Arg 340 345 350 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pro Tyr Trp Pro Glu Val 355 360 365 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Val Thr Asn Cys Gly Glu 370 375 380 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Leu Gln Val Ser Pro Leu 385 390 395 400 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp His Tyr Gln Tyr Leu Ser 405 410 415 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gly Gly Val Leu Ser Phe 420 425 430 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Leu Pro His Ala Gly Pro 435 440 445 Ile Ile Val His Cys Ser Ala Gly Ile Gly Arg Thr Gly Thr Ile Ile 450 455 460 Val Ile Asp Met Leu Met Glu Asn Ile Ser Thr Lys Gly Leu Asp Cys 465 470 475 480 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Val Arg Ala Gln Arg Ser 485 490 495 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Phe Ile Tyr Val Ala Ile 500 505 510 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Leu Glu Val Leu Gln Ser 515 520 525 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Ile Thr Tyr Pro Pro Ala 530 535 540 Met Lys Asn Ala His Ala Lys Ala Ser Arg Thr Ser Ser Lys His Lys 545 550 555 560 Glu Asp Val Tyr Glu Asn Leu His Thr Lys Asn Lys Arg Glu Glu Lys 565 570 575 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Lys Ser Lys Gly Ser Leu 580 585 590 Lys Arg Lys 595 <210> SEQ ID NO 92 <211> LENGTH: 4301 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 387, 388, 3718, 3799, 4224 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 92 ccgaaggggg aagattgctt gagctcagga gtttaaaacc agcctgggca acatagagag 60 accccatctc tattaaaaaa aaatactggg tatgatggcc caagcatgtg gtagtcctag 120 cagtttggga gtctgaggtg ggaggatcac ttgagcccaa gagttcaaga ccaccctggg 180 caacataggg agagacctca tctctactac gactacgact actactacta ctaataaata 240 gctggatgta gtggcatgca cctgtggtct cagttacttg gaaggctgag gcaggaggat 300 cacctgaccc aaggaggtcg acgctgcagt gagttggatt gtgacactgc acttcagcct 360 gggtgataaa gcaagattct gtgtccnnaa aaaaaaaaaa aagagaggga aggaaagaag 420 gaagggaagg aagaaagaaa aagagaaaga aggaaaaaaa ggaaagagcg agaaagaaga 480 aagaaaagga aggaaggaaa gaaagaaaag aaaggaaaga aaaagaaaaa gtgacaccca 540 gtcgaaagaa gaaaggaaag aaaaagaaaa agtgacaacc ggtcgaaaga aaaaagaaaa 600 agtgacaacc ggctgggcat ggtggctcaa gcctgtaatc ccagcacttt gggaggccga 660 ggcaggtgga tcacgaggtc aggagttcaa gaccagcctg gccaacatgg tgaaaccctg 720 tctcaactaa agatacaaaa aaaaaattag gctggcacag tggtgcgcac ctgtgagtcc 780 cagctactag ggaggctgag gcaggagaat tgcttgaacc caggaggcgg aggttgcagt 840 gagccgagat tgcgtcactg cactccagcc tgagtgcagc gggagagact ccatctcaaa 900 aaaaaaaaaa aaagaaaaga aaaagtgaca acctgcttac agagtactgg cgagtttgtg 960 ggtgggtggc tccctagccc tgctgattct tgcttctcac actcatgtct gcccctgccc 1020 cagtgcacat cttgtcactg tcggccccac cgatggggtt cctactgagt cttctggtcc 1080 ctgatcccgt ctgtggtcat tttcctgcca ggtagcttgg ccaggcctcc cctggtgcag 1140 atttcatcct tggtttctca gcctggcctt gaatgaccct ctacagcagg gtccccacct 1200 ctcagaacaa ctttgctcca gccacatggc ttgctcacgg ccaggcactg cccatgtgga 1260 ctctgtgcgt gccacctctt tgccctgacc catgttgcct ctgggggagc acttcttcct 1320 ccaccttcca tcatgggctg tggcagtgcc catcccatct gcccccgacg ctgtctgctg 1380 cagtatggtt gttgggggaa agggcaccag gctccggcgt ctgacagccg tgttttaccc 1440 accttcctac tcactagctt gtgaccttgg gcaattactt aacatctctg agtcttagtt 1500 tctgtttcta aaattgggtg aataacacct actaagtagg gttggcctga ggattaatag 1560 tataatgtaa aagctggcag cactgaaacc ctgccactta ccagcttttc acatcagtat 1620 ttgggaaata ttgttaagct catttgtcag gcggggattc tgaggctcag agcagttcca 1680 gaactttcta cagattattt tgccttgttt gcgcttccag actgcctatc ttcttgtatc 1740 accattgatc ttgatctgta tggtttttaa tttttttttt tttgagacgg agtttcactc 1800 tgttgcccag gctggagtgc ggtggcatga tctcggctca ctgcaacctc cacctcctga 1860 gaagctggga ttacaggcat gtgccaccac acccggctaa tctttgtatt tttagtagag 1920 ttggggtttc actatgttgg ccaggctggt ctcgatctcc tgacctcgtg atccgccagc 1980 cttggcctcc caaagtgctg ggattacagg cgtgagccac tgcgcccggc caacttcacg 2040 tttatacaca cccatgcaaa cagcatccag atagagacaa agagccttcc ctgtacccta 2100 aaagtttccc agaaattgtt cccagttagc atatttattt ttataaaggt aatgcatgcc 2160 catcatataa cattcaaaaa ggtatgtaga gaaccaagtg tctcccccag ccctgtcctc 2220 cagccaccca gtttccctcc ctaggggaag ccaccaatat gtgtttctta tgtatcccct 2280 gttgagctgc ttttcctcgt tttggtttgg cggtgttgat gtttgtattt ggaattacag 2340 gtaggcagca tcatatacct tagtgtttag ggcctctaag atcaaccagc cctgagaaaa 2400 tcagccatgg tgaggacctt gtcccccagc cccccaggag ataggccccc tggtgggagt 2460 gctggggcag ggcagaggcc tagggacaag aattagaaag gacccatgtt gacagggctg 2520 ctcagggtca tgttgtccat ccctctgcca cagtggcatg gacaaactgc atatgttggt 2580 tagaggaggg cacccttctc tcttgcaagc attggcaagg tcttaactat tagtctcctg 2640 ctcccatggc agcccctttg gacaaggagg ctcttaatct ctgttctttg aagccctgag 2700 ggctggtgta taggagttca aagcactggc tttggaaccg gactgtctgg gtttgaatcc 2760 tggcactgca gctgactcac tgatggactc aggcaatgcc ttaaactccc tgagcctcag 2820 gttccttgtc tgtaaaatga taaagatagc ccctgtttca tagggctgtg gtgagaaacc 2880 aatcagacaa ggcatgtgaa cgccattata gcacagcgcc cggcatccag caggactcac 2940 tcgatgacag ttgtcaccgc catcattgtt attagcgtgg gccagggagg gctgcgtaaa 3000 agcagctggt ggaggaggga gagatgccgt gggaccgtct gggttcgcat gcgtgaagta 3060 ttatctgggc ctggagtgtg caaggcacac atgtgtcctt actgcatgtg ttgtcacata 3120 tgtgcaatgc catgctcctg agcctttgat tgcagacgtg tgggaagtgg gccccgtccc 3180 cacccccagt gccaccctgc tctgcttctc ttcccttgct gtgctctaaa acgagaagta 3240 caagtgagtt cccccaaggg gtcggccgcg cctcttcctg tccccgccct gccggctgcc 3300 ccaggccagt ggagtggcag ccccagaact gggaccaccg ggggtggtga ggcggcccgg 3360 cactgggagc tgcatctgag gcttagtccc tgagctctct gcctgcccag actagctgca 3420 cctcctcatt ccctgcgccc ccttcctctc cggaagcccc caggatggtg aggtaagggc 3480 ctgccaccca cggtagacag gaggcaaggg tgcctggtgc ccacgggacc cctcctcact 3540 gccctgcctg ggccgcccag gtggtttcac cgagacctca gtgggctgga tgcagagacc 3600 ctgctcaagg gccgaggtgt ccacggtagc ttcctggctc ggcccagtcg caagaaccag 3660 ggtgacttct cgctctccgt caggtaggtg ggccccccgc aaccccgggc attttggnca 3720 ctctcttgtg ccatccaggc cctgaaccac tcattcctgg ttccccgtgg cagtgctgac 3780 tccccgtctg ttcccttgnc cccaaccccc acactcccca tccctgtctg tgcccaccca 3840 tgcccatgtg tgcccccacc caggacctca gccgatccct gccctcctgc ctctactcct 3900 gcaccgactg gcctcaccgc ctggtgccct gcagggtggg ggatcaggtg acccatattc 3960 ggatccagaa ctcaggggat ttctatgacc tgtatggagg ggagaagttt gcgactctga 4020 cagagctggt ggagtactac actcagcagc agggtgtcct gcaggaccgc gacggcacca 4080 tcatccacct caagtacccg ctgaactgct ccgatcccac tagtgagagg tgagggctcc 4140 gcacccccgc cattcccaag cagggatgag ccggctccca ccctgaacag ccagggaggc 4200 agggagactg gcagccggcg ctgnctaccc tccatcccct cccctccctg caccagctgg 4260 ggctctcaat gtccctcctc cctgctgtcc tgggacctgg t 4301 <210> SEQ ID NO 93 <211> LENGTH: 8545 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 1958, 2678, 3190, 4689, 4712, 5166, 5632, 5777, 7758, 8183 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 93 actccctctt gcaggtgtcc ttaagtttgc tcgcttggtc aagtcctacg aagcccagga 60 tcctgagatc gccagcctgt caggcaagct gaaggcgctg tttctgccgc ccatgaccct 120 gccaccccat gggcctgctg ctggtggcag cgtggccgcc tcctgagagt tggccctccc 180 ttgtgccact gccaggggag gaaaggcctt gatgttccag acaataataa atgcgcctgt 240 gacttagcct tggtgtcagt ctcttgcgga cctgacaacc cccatctctc cttccctgat 300 tccctctgcc tttccaggcc ccatccccct gaacagctcc tccctatggt cctggctggg 360 cctaaccctg ccccagggcc taaccctacc tgaggctcct ccccttcccc cggggcaggt 420 tgagaggctg gagtgggtcc ctcagcgccc tgggtgggtg ggcctgcaca gggggtacct 480 ccttctctga ggaactgggc tgttagggat tttccttagg ccctttggtt tccgcctacg 540 gagaggtttc ccccattggt tgctcttcct cagccagggt tacttcctgg tctgttcccc 600 tacccaatac cccgccgctc tgtcagcttg agctccaggt ggagctccag gtggctcctc 660 ctctcccggg ggaaggcggc cctggaccag caggcgggcc tgctgtactc ccgctttggg 720 gctgcaggga agctggccgc tgtgggcggt ctcgggccag ccccgcccca cctgtccttt 780 tcctggagac tattagtcca gggtttgtcc ctgcagtgcc attggcctgg caggcaggat 840 cgaggaggaa gtggctgatt actgagcggt tcttcctcac ctggcttggg ccactgtgca 900 cagctgtgcc gctggctcag ccccgccccc tgcggccctc cgccgtggct tccccctccc 960 tacagagaga tgctgtcccg tgggtaagtc ccgggcacca tcggggtccc agtctcctgt 1020 tagttttgga gggagggagg gctttgttga tgctcactcc gacgtgtgtg aacgtgagtg 1080 cgatctgccg ctgccctgcg cctgtttccg gtccctatga acttcccctt cccgcaaggt 1140 gtgaggaccc ccggctcact catgctcctc tgccccctct ttaacatttt cccctggaca 1200 agtgtgtatc tgttctctcc attgcatttc tacttccagc ctctgggctc ctgcttctgc 1260 ctcctgctta ggacctgtcc ccctgggtag ctcacaacac ctcaaacata gcagtcagag 1320 gccacccgcg aaggccctcc cacgtccagc caacttctcc gcacttccca acatcagact 1380 ttggtcccat cttctttgtt tcctttcact tccctttccc ctgcatcatt cattcaacag 1440 gtacgtgttg agcatctatt atgcaccagg tgctgtttaa gatgctggta atactggagt 1500 gaacaagaca gacatggtct ctgctctcac ggagcttaca ttccagtggg aggttacaga 1560 ccgaacaaat aacccaataa attggatcat tgcagattct cagaagtatt acgcagaaaa 1620 tagacagcct tggccgggtg tagtggttca cacctgtgat cccagcactg tgggaggctg 1680 aggcgagagg attgcttgag cccaggagtt tgagaccagc ctggccaata tagtgagacc 1740 ctgtctctac aaaaaataag aaattagctg ggtgtggtgg cacacgtcct gtggttccag 1800 ctatggagag gctaaggtga gaggcttgct tgagcctggg aggtcaaggc tgcagtcagc 1860 gatgattgca ccactgcaca ccagcctggg cgacagagtg agaccttgtc tcaaaaaaaa 1920 aaaaaaaaaa gaaaatgaac cagcttcata tgctagcnag tgactgggtg tgcaggtgac 1980 attactagct ggagggatca gggaggcctt cccgaggagg tgacatttga gctgagaccc 2040 ggatgaggag gaagaggagc tggccatgtg acgtagtgat caagagtcaa gcatctctgg 2100 gcagaggaga tggtgagcac aaagccctaa tgtgggaaca aacaaaaaaa ggacagtgtg 2160 cccgtggcag aggaccctag tggagcggag gcagggccac agcaggttag accatgttgg 2220 agctaggatg ttgaaagtga aaacctgacg agatgaggtg gcgcacgtct gtgatcccag 2280 cactttggga ggccgaaggg ggaagattgc ttgagctcag gagtttaaaa ccagcctggg 2340 caacatagag agaccccatc tctattaaaa aaaaatactg ggtatgatgg cccaagcatg 2400 tggtagtcct agcagtttgg gaggctgagg tgggaggatc acttgagccc aagagttcaa 2460 gaccaccctg ggcaacatag ggagagacct catctctact acgactacga ctactattac 2520 tactaataaa tagctggatg tagtggcatg cacctgtggt ctcagttact tggaaggctg 2580 aggcaggagg atcacctgag ccaaggaggt cgacgctgca gtgagttgga ttgtgacact 2640 gcacttcagc ctgggtgata aagcaagatt ctgtgtcnaa aaaaaaaaaa aaaagagagg 2700 gaaggaaaga aggaagggaa ggaagaaaga aaaagagaaa gaaggaaaaa aaggaaagag 2760 cgagaaagaa gaaagaaaag gaaggaagga aagaaagaaa agaaaggaaa gaaaaagaaa 2820 aagtgacacc cagtcgaaag aagaaaggaa agaaaaagaa aaagtgacaa ccggtcgaaa 2880 gaaaaaagaa aaagtgacaa ccggctgggc atggtggctc aagcctgtaa tcccagcact 2940 ttgggaggcc gaggcaggtg gatcacgagg tcaggagttc aagaccagcc tggccaacat 3000 ggtgaaaccc tgtctcaact aaagatacaa aaaaaaaatt aggctggcac agtggtgcgc 3060 acctgtgagt cccagctact agggaggctg aggcaggaga attgcttgaa cccaggaggc 3120 ggaggttgca gtgagccgag attgcgtcac tgcactccag cctgagtgca gcgggagaga 3180 ctccatctcn aaaaaaaaaa aaaaagaaaa gaaaaagtga caacctgctt acagagtact 3240 ggcgagtttg tgggtgggtg gctccctagc cctgctgatt cttgcttctc acactcatgt 3300 ctgcccctgc cccagtgcac atcttgtcac tgtcggcccc accgatgggg ttcctactga 3360 gtcttctggt ccctgatccc gtctgtggtc attttcctgc caggtagctt ggccaggcct 3420 cccctggtgc agatttcatc cttggtttct cagcctggcc ttgaatgacc ctctacagca 3480 gggtccccac ctctcagaac aactttgctc cagccacatg gcttgctcac ggccaggcac 3540 tgcccatgtg gactctgtgc gtgccacctc tttgccctga cccatgttgc ctctggggga 3600 gcacttcttc ctccaccttc catcatgggc tgtggcagtg cccatcccat ctgcccccga 3660 cgctgtctgc tgcagtatgg ttgttggggg aaagggcacc aggctccggc gtctgacagc 3720 cgtgttttac ccaccttcct actcactagc ttgtgacctt gggcaattac ttaacatctc 3780 tgagtcttag tttctgtttc taaaattggg tgaataacac ctactaagta gggttggcct 3840 gaggattaat agtataatgt aaaagctggc agcactgaaa ccctgccact taccagcttt 3900 tcacatcagt atttgggaaa tattgttaag ctcatttgtc aggcggggat tctgaggctc 3960 agagcagttc cagaactttc tacagattat tttgccttgt ttgcgcttcc agactgccta 4020 tcttcttgta tcaccattga tcttgatctg tatggttttt aatttttttt tttttgagac 4080 ggagtttcac tctgttgccc aggctggagt gcggtggcat gatctcggct cactgcaacc 4140 tccacctcct gagaagctgg gattacaggc tagtagagat ggggttccac tgtgttgccc 4200 agctggtctc gaactcctga cctcaagtga tcctcccacc tcggcctccc aaagtgctgg 4260 gattacaggt gtaagtcact gcgcccagct gtatttttat tttttgagac agggtctcac 4320 tctgtcaccc aggccggatt acagtggcac aaccatggct cactgcagcc tcgaccaccc 4380 caggctcaag cgatcctccc atctcagtct cccaagtacc tggggctaca ggggtgtgct 4440 accacacctg gctaaatttt gtattttttg tagagacagg gtttctccag gtttcctagg 4500 ctgctctcaa acttggtgtc aagtaatcca ccagcctcac ccccacaaag tgctgggatt 4560 acaggcgtga gccactgcgc ctggccttga tctctacttt tatcttcctg cttccaagga 4620 aatatttttt tcttctgaat tatcaggcat ttactcttgt aattcttagt ctccctacgc 4680 ttgtttccnc ccataagaaa atggggaaaa tnattcctac atcacagggc tgtctgaggc 4740 ctaaatgaga tcgtgtatgt gaaagtgatc tgcaaacccc acaccatgcc aaggtaaggg 4800 aggtagtttt ttattttcct gccaaaggat agcagaagct gtacctcttg tctgagttct 4860 gtctcttggc ttgacaccct tcagaggaat tcctgcctct tccatgggtc aggaagaggt 4920 gcctagttag tttcttctgg gtgccgagtt aattccttcc caccaagtgg gtttaagccc 4980 tggaaggagt gtcttggggc cagggtgcag tgggcgtttg gtgctgagca tggacctgaa 5040 acttcgtgtg tggtcagatt tatgttccat gcgtggggat gtgcaccgga ccaggtatgt 5100 gtgtaggtgg acatggatga tgaggtgtgt gtgctgtgac tgtgtgtgca cccttgcctg 5160 cgtatnacaa gcaggctgtg tgtgtaggac caggaagctg tacttgtggc caggtatgtg 5220 gctatggact gacgagcttg tttgttgaac acttgctcag tgccaggcat cgcactggac 5280 tctgaacact ccgagatgag cgagagcgcc agcgggtgtc ccgcgctgca gccagctttg 5340 catgtgctct tcttgctcct tggcgttggg cgtgggggtt ccgcggattt ccggggctct 5400 ggggtggtgt ccaagctgaa ggggtagtca aagctggacc atgcaataaa cccaccaggc 5460 agattcccca gggcaccagt gagagaagaa aaccagaaac aaatagaaca aaaagaaaga 5520 aagaaaagtg gaaaagcctt ttttggggga aaacattgat gtttgatgtt tctaaaaatg 5580 ataatgtagt tatcatggga aaattagact tgttgggctt aaaacttttt cntcttttac 5640 ctgaagcaga acatgcataa tgttcataaa tattaagcac acaacctggc tccatttttt 5700 tttttttttt gaaatagagt cttactgtgt tgccaggctg gagtgcagtg gtgtgatctt 5760 ggctcgctgc aacctcngct tcctgggttc aagtgattct cctgcttcaa cctcccgagt 5820 agctgggatt acaggcgccc accaccatgc ccagctaatt tttttgtatt tttagtagag 5880 agggggtttc accatgttgg ccaggatggt ctcgatctcc tgacctcgtg atccgccagc 5940 cttggcctcc caaagtgctg ggattacagg cgtgagccac tgcgcccggc caacttcacg 6000 tttatacaca cccatgcaaa cagcatccag atagagacaa agagccttcc ctgtacccta 6060 aaagtttccc agaaattgtt cccagttagc atatttattt ttataaaggt aatgcatgcc 6120 catcatataa cattcaaaaa ggtatgtaga gaaccaagtg tctcccccag ccctgtcctc 6180 cagccaccca gtttccctcc ctaggggaag ccaccaatat gtgtttctta tgtatcccct 6240 gttgagctgc ttttcctcgt tttggtttgg cggtgttgat gtttgtattt ggaattacag 6300 gtaggcagca tcatatacct tagtgtttag ggcctctaag atcaaccagc cctgagaaaa 6360 tcagccatgg tgaggacctt gtcccccagc ccccaggaga taggccccct ggtgggagtg 6420 ctggggcagg gcagaggcct agggacaaga attagaaagg acccatgttg acagggctgc 6480 tcagggtcat gttgtccatc cctctgccac agtggcatgg acaaactgca tatgttggtt 6540 agaggagggc acccttctct cttgcaagca ttggcaaggt cttaactatt agtctcctgc 6600 tcccatggca gcccctttgg acaaggaggc tcttaatctc tgttctttga agccctgagg 6660 gctggtgtat aggagttcaa agcactggct ttggaaccgg actgtctggg tttgaatcct 6720 ggcactgcag ctgactcact gatggactca ggcaatgcct taaactccct gagcctcagg 6780 ttccttgtct gtaaaatgat aaagatagcc cctgtttcat agggctgtgg tgagaaacca 6840 atcagacaag gcatgtgaac gccattatag cacagcgccc ggcatccagc aggactcact 6900 cgatgacagt tgtcaccgcc atcattgtta ttagcgtggg ccagggaggg ctgcgtaaaa 6960 gcagctggtg gaggagggag agatgccgtg ggaccgtctg ggttcgcatg cgtgaagtat 7020 tatctgggcc tggagtgtgc aaggcacaca tgtgtcctta ctgcatgtgt tgtcacatat 7080 gtgcaatgcc atgctcctga gcctttgatt gcagacgtgt gggaagtggg ccccgtcccc 7140 acccccagtg ccaccctgct ctgcttctct tcccttgctg tgctctaaaa cgagaagtac 7200 aagtgagttc ccccaagggg tcggccgcgc ctcttcctgt ccccgccctg ccggctgccc 7260 caggccagtg gagtggcagc cccagaactg ggaccaccgg gggtggtgag gcggcccggc 7320 actgggagct gcatctgagg cttagtccct gagctctctg cctgcccaga ctagctgcac 7380 ctcctcattc cctgcgcccc cttcctctcc ggaagccccc aggatggtga ggtaagggcc 7440 tgccacccac ggtagacagg aggcaagggt gcctggtgcc cacgggaccc ctcctcactg 7500 ccctgcctgg gccgcccagg tggtttcacc gagacctcag tgggctggat gcagagaccc 7560 tgctcaaggg ccgaggtgtc cacggtagct tcctggctcg gcccagtcgc aagaaccagg 7620 gtgacttctc gctctccgtc aggtaggtgg gccccccgca accccgggca ttttggccac 7680 tctcttgtgc catccaggcc ctgaaccact cattcctggt tccccgtggc agtgctgact 7740 ccccgtctgt tcccttgncc ccaaccccca cactccccat ccctgtctgt gcccacccat 7800 gcccatgtgt gcccccaccc aggacctcag ccgatccctg ccctcctgcc tctactcctg 7860 caccgactgg cctcaccgcc tggtgccctg cagggtgggg gatcaggtga cccatattcg 7920 gatccagaac tcaggggatt tctatgacct gtatggaggg gagaagtttg cgactctgac 7980 agagctggtg gagtactaca ctcagcagca gggtgtcctg caggaccgcg acggcaccat 8040 catccacctc aagtacccgc tgaactgctc cgatcccact agtgagaggt gagggctccg 8100 cacccccgcc attcccaagc agggatgagc cggctcccac cctgaacagc cagggaggca 8160 gggagactgg cagccggcgc tgnctaccct ccatcccctc ccctccctgc accggctggg 8220 gctctcaatg tccctcctcc ctgctgtcct gggacctggt gtctcagagc ctaacctacc 8280 accctttcca cctaaccccg aggaagccac agaaagctgc ctcgccctac tccgggagcc 8340 ctggccgctg caacccaggt cccactggag acagggaggc cactgctggt ggccagcatg 8400 tcgtgcaggc cagctctgtt gttagaaagc tcttcttcct ctggaatcga gcctgccttc 8460 ctccgtctgt ccctcacccc aggacatgtt aggacagtga ggagctgaca ctgggggtga 8520 agatggggat gaattgcttg gcaag 8545 <210> SEQ ID NO 94 <211> LENGTH: 2734 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 94 cctccagcac gctgtgctcc tgcagcagca gtggcttctt ggtgctgcct tggccatgac 60 acatatttga catgccctcc cttaacctac tcacagactc ttgctctgcg gcatggacca 120 aagagaaatt ctgcagcaac tactgaaaga agcccagaaa aagaaactca acagtgagga 180 gtttgccagt gaatttctga agctgaaaag gcaatccacc aagtacaagg ccgacaaaat 240 ctatcctaca actgtggctc agaggcccaa gaatatcaag aaaaacagat acaaggatat 300 tttgccctat gatcacagcc tggtagagct gtctctgtta acttccgatg aggattccag 360 ttatatcaat gccagcttta ttaagggtgt ctatggaccc aaggcttata ttgctaccca 420 gggtccttta tctacaactc tcctggactt ctggaggatg atttgggagt accgcatctt 480 ggtcattgtc atggcatgta tggagtttga aatgggaaag aaaaaatgtg agcgttattg 540 ggccgaacca ggagaaacgc agctgcaatt tggccccttt tctatatcct gtgaagctga 600 gaaaaagaaa tctgattata aaatcaggac tctgaaggcc aagttcaata atgaaactcg 660 aattatttac cagtttcatt ataagaattg gccagaccat gatgtgcctt catctataga 720 ccctattctt cagctcatct gggatatgcg ttgttaccaa gaagatgact gtgttcctat 780 atgcattcac tgcagtgccg gctgcggaag gacaggtgtc atttgtgctg ttgattatac 840 atggatgctg ctgaaagatg ggataattcc taagaacttc agtgttttta atttgattca 900 ggagatgcga acacagaggc cttcgctagt tcaaactcag gaacagtacg aactggtcta 960 cagtgctgtg ttagagctgt ttaagaggca catggatgtt atctctgata atcaccttgg 1020 aagagagatt caagcacaat gctcaattcc tgaacaaagc ctcacggtag aagctgactc 1080 ttgtcctctg gatttaccaa aaaacgccat gagggatgtg aaaacgacaa accagcatag 1140 caaacaaggg gctgaagcgg agagcactgg agggtcttcc cttggcctta ggacttctac 1200 gatgaatgcc gaggaagagt tggttttgca ctcggctaaa tcaagccctt cttttaactg 1260 tttagagcta aactgcgggt gtaacaacaa ggctgtcata accaggaacg ggcaggcaag 1320 ggcttctcca gtcgtgggag agccccttca gaagtatcaa agtctggatt ttggttccat 1380 gttgtttggg tcgtgtccta gtgctctgcc cataaacaca gcggacaggt atcacaattc 1440 aaaggggccg gtaaaacgga ccaaatcaac tccctttgaa ctgattcagc agagaaaaac 1500 aaatgacttg gccgtgggag acggtttttc atgcctggaa tctcagctgc atgagcatta 1560 cagtctcagg gagctgcagg tgcaaagagt ggcccatgtt tcttcagaag agctgaatta 1620 ttcactgcct ggtgcctgtg atgcgtcgtg tgtgccccgg cacagccccg gcgctttgag 1680 agtgcatctg tacacatctt tagcggaaga tccttatttt tcatcatccc ctccgaatag 1740 tgctgattcg aagatgtctt ttgatctgcc tgagaaacag gatggagcca cttcccctgg 1800 cgctctattg ccagcctctt ctacaacctc cttcttttat agcaacccac acgactccct 1860 agtgatgaac actctgacca gcttttcccc accgttaaac caagagacag ctgtagaagc 1920 tccttctcgg aggacagatg atgaaatccc cccgccactc cctgaacgga cacccgagtc 1980 ttttattgtg gttgaggaag ccggagagcc ctcaccacgt gttaccgaat ccttacctct 2040 ggtggtaaca tttggagcat caccagaatg cagtgggaca tctgaaatga agagccatga 2100 ctctgtaggg tttacaccaa gcaagaatgt gaaactccga agtcccaaat cagatcgaca 2160 tcaggatggt tctcctccac ctcctctccc agaaagaact ctagagtcct tctttcttgc 2220 tgatgaggac tgtatacagg cccaagccgt gcaaacttct tctactagct atcctgaaac 2280 cacagagaac tccacatctt ctaaacaaac attgaggacc cctggaaaaa gtttcacaag 2340 gagtaagagt ttgaagattt ttcgaaatat gaaaaaaagt gtttgtaatt cttcctcacc 2400 aagcaagcct acagaacgtg ttcagccaaa aaattccagc tcctttctga attttggttt 2460 cggaaatcgt ttttcaaaac ccaaaggacc aaggaacccg ccatcagctt ggaatatgta 2520 acgcacctct ggatttataa gaatatttgt taaaattgta cctgcagata aagctacttg 2580 aatactgcta taataataat atcagtaatg aggatatatt ttgtcaatag tcttgaaaag 2640 gaaagcaata tgtgacaaac ttccagcaaa cttgtatttt catattcctt atatttcact 2700 gggaactgcc aataaagttt gtacttcaaa aaaa 2734 <210> SEQ ID NO 95 <211> LENGTH: 802 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 95 Met Asp Gln Arg Glu Ile Leu Gln Gln Leu Leu Lys Glu Ala Gln Lys 1 5 10 15 Lys Lys Leu Asn Ser Glu Glu Phe Ala Ser Glu Phe Leu Lys Leu Lys 20 25 30 Arg Gln Ser Thr Lys Tyr Lys Ala Asp Lys Ile Tyr Pro Thr Thr Val 35 40 45 Ala Gln Arg Pro Lys Asn Ile Lys Lys Asn Arg Tyr Lys Asp Ile Leu 50 55 60 Pro Tyr Asp His Ser Leu Val Glu Leu Ser Leu Leu Thr Ser Asp Glu 65 70 75 80 Asp Ser Ser Tyr Ile Asn Ala Ser Phe Ile Lys Gly Val Tyr Gly Pro 85 90 95 Lys Ala Tyr Ile Ala Thr Gln Gly Pro Leu Ser Thr Thr Leu Leu Asp 100 105 110 Phe Trp Arg Met Ile Trp Glu Tyr Arg Ile Leu Val Ile Val Met Ala 115 120 125 Cys Met Glu Phe Glu Met Gly Lys Lys Lys Cys Glu Arg Tyr Trp Ala 130 135 140 Glu Pro Gly Glu Thr Gln Leu Gln Phe Gly Pro Phe Ser Ile Ser Cys 145 150 155 160 Glu Ala Glu Lys Lys Lys Ser Asp Tyr Lys Ile Arg Thr Leu Lys Ala 165 170 175 Lys Phe Asn Asn Glu Thr Arg Ile Ile Tyr Gln Phe His Tyr Lys Asn 180 185 190 Trp Pro Asp His Asp Val Pro Ser Ser Ile Asp Pro Ile Leu Gln Leu 195 200 205 Ile Trp Asp Met Arg Cys Tyr Gln Glu Asp Asp Cys Val Pro Ile Cys 210 215 220 Ile His Cys Ser Ala Gly Cys Gly Arg Thr Gly Val Ile Cys Ala Val 225 230 235 240 Asp Tyr Thr Trp Met Leu Leu Lys Asp Gly Ile Ile Pro Lys Asn Phe 245 250 255 Ser Val Phe Asn Leu Ile Gln Glu Met Arg Thr Gln Arg Pro Ser Leu 260 265 270 Val Gln Thr Gln Glu Gln Tyr Glu Leu Val Tyr Ser Ala Val Leu Glu 275 280 285 Leu Phe Lys Arg His Met Asp Val Ile Ser Asp Asn His Leu Gly Arg 290 295 300 Glu Ile Gln Ala Gln Cys Ser Ile Pro Glu Gln Ser Leu Thr Val Glu 305 310 315 320 Ala Asp Ser Cys Pro Leu Asp Leu Pro Lys Asn Ala Met Arg Asp Val 325 330 335 Lys Thr Thr Asn Gln His Ser Lys Gln Gly Ala Glu Ala Glu Ser Thr 340 345 350 Gly Gly Ser Ser Leu Gly Leu Arg Thr Ser Thr Met Asn Ala Glu Glu 355 360 365 Glu Leu Val Leu His Ser Ala Lys Ser Ser Pro Ser Phe Asn Cys Leu 370 375 380 Glu Leu Asn Cys Gly Cys Asn Asn Lys Ala Val Ile Thr Arg Asn Gly 385 390 395 400 Gln Ala Arg Ala Ser Pro Val Val Gly Glu Pro Leu Gln Lys Tyr Gln 405 410 415 Ser Leu Asp Phe Gly Ser Met Leu Phe Gly Ser Cys Pro Ser Ala Leu 420 425 430 Pro Ile Asn Thr Ala Asp Arg Tyr His Asn Ser Lys Gly Pro Val Lys 435 440 445 Arg Thr Lys Ser Thr Pro Phe Glu Leu Ile Gln Gln Arg Lys Thr Asn 450 455 460 Asp Leu Ala Val Gly Asp Gly Phe Ser Cys Leu Glu Ser Gln Leu His 465 470 475 480 Glu His Tyr Ser Leu Arg Glu Leu Gln Val Gln Arg Val Ala His Val 485 490 495 Ser Ser Glu Glu Leu Asn Tyr Ser Leu Pro Gly Ala Cys Asp Ala Ser 500 505 510 Cys Val Pro Arg His Ser Pro Gly Ala Leu Arg Val His Leu Tyr Thr 515 520 525 Ser Leu Ala Glu Asp Pro Tyr Phe Ser Ser Ser Pro Pro Asn Ser Ala 530 535 540 Asp Ser Lys Met Ser Phe Asp Leu Pro Glu Lys Gln Asp Gly Ala Thr 545 550 555 560 Ser Pro Gly Ala Leu Leu Pro Ala Ser Ser Thr Thr Ser Phe Phe Tyr 565 570 575 Ser Asn Pro His Asp Ser Leu Val Met Asn Thr Leu Thr Ser Phe Ser 580 585 590 Pro Pro Leu Asn Gln Glu Thr Ala Val Glu Ala Pro Ser Arg Arg Thr 595 600 605 Asp Asp Glu Ile Pro Pro Pro Leu Pro Glu Arg Thr Pro Glu Ser Phe 610 615 620 Ile Val Val Glu Glu Ala Gly Glu Pro Ser Pro Arg Val Thr Glu Ser 625 630 635 640 Leu Pro Leu Val Val Thr Phe Gly Ala Ser Pro Glu Cys Ser Gly Thr 645 650 655 Ser Glu Met Lys Ser His Asp Ser Val Gly Phe Thr Pro Ser Lys Asn 660 665 670 Val Lys Leu Arg Ser Pro Lys Ser Asp Arg His Gln Asp Gly Ser Pro 675 680 685 Pro Pro Pro Leu Pro Glu Arg Thr Leu Glu Ser Phe Phe Leu Ala Asp 690 695 700 Glu Asp Cys Ile Gln Ala Gln Ala Val Gln Thr Ser Ser Thr Ser Tyr 705 710 715 720 Pro Glu Thr Thr Glu Asn Ser Thr Ser Ser Lys Gln Thr Leu Arg Thr 725 730 735 Pro Gly Lys Ser Phe Thr Arg Ser Lys Ser Leu Lys Ile Phe Arg Asn 740 745 750 Met Lys Lys Ser Val Cys Asn Ser Ser Ser Pro Ser Lys Pro Thr Glu 755 760 765 Arg Val Gln Pro Lys Asn Ser Ser Ser Phe Leu Asn Phe Gly Phe Gly 770 775 780 Asn Arg Phe Ser Lys Pro Lys Gly Pro Arg Asn Pro Pro Ser Ala Trp 785 790 795 800 Asn Met <210> SEQ ID NO 96 <211> LENGTH: 2176 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 96 gaattcggca cgagaggggc ttggctcaaa gtgccattgg tttgacaggc tggatgagga 60 ggaagtggcc gaaaccgaaa tattcttcct gaaggtctgg atccccgaac agctgtgcca 120 ctcgattggc cccgcccctg tcgccctttg cctgtgactt cccccactcc tccagggaga 180 tgctgtcccg cgggtggttt caccgggacc tcagtgggcc tgatgccgag accctgctca 240 agggccgggg agtccctggg agcttcctgg ctcggcccag tcgcaagaac cagggtgact 300 tctccctctc agtcagggtg gatgaccagg tgactcatat tcggatccag aactcagggg 360 acttctatga cctgtatgga ggggagaagt ttgcgacgtc gacagagctg gtggagtatt 420 acactcagca gcagggcatc ctgcaggacc gagacggcac catcatccac ctcaagtacc 480 cactgaactg ctcggacccc accagcgaga ggtggtatca tggtcacatg tctggagggc 540 aggcagagtc actgctgcag gccaagggcg agccctggac atttcttgtg cgtgagagtc 600 tcagccaacc tggtgatttt gtgctctctg tgctcaatga ccagcccaag gctgccccgg 660 gttccccgct cagggtcacg cacatcaagg ttatgtgtga gggtggacga tacactgtgg 720 gtggctcaga gacattcgac agcctcacag acctggtgga gcacttcaag aagacgggga 780 ttgaggaggc ctcaggtgcc tttgtctacc tgaggcagcc ttactatgcc actcgggtaa 840 atgcagcaga cattgagaac cgggtcttgg aactgaacaa gaagcaggag tcagaggaca 900 cagccaaggc cggcttctgg gaggagtttg agagtctgca aaagcaagag gcaaagaact 960 tgcaccagcg tctggaaggg cagcggccgg agaacaagag caagaaccgc tacaagaaca 1020 ttcttccctt tgaccacagc cgagtgatcc tgcagggacg tgacagtaac atcccagggt 1080 ctgattacat caatgccaac tacgttaaga accagctgct aggtccggat gagaactcta 1140 agacctacat cgccagtcag ggctgtctgg acgctaccgt caatgacttc tggcagatgg 1200 cttggcagga gaacactcgt gtcatcgtca tgactaccag agaggtggag aaaggccgga 1260 acaaatgtgt cccatactgg cctgaggtgg gcactcagcg cgtctatggg ctctactctg 1320 tgaccaactg taaagagcat gacacagcag agtacaaact tcgaacattg cagatctccc 1380 cactggacaa tggggacctg gttcgggaga tatggcacta ccagtacctg agctggcctg 1440 accatggggt tcccagtgag cctggaggtg tcctcagctt tctggatcag atcaaccagc 1500 ggcaggaaag tttgcctcac gcggggccca tcattgtgca ttgcagcgct ggcatcggcc 1560 gcaccggcac catcatcgtc attgatatgc tcatggagag cgtctccacc aaggggctag 1620 actgtgacat tgacatccag aagaccatcc agatggtacg ggcacagcgc tctggcatgg 1680 tgcagacaga ggcacagtac aagtttattt atgtggccat cgcccagttc atcgaaacaa 1740 ccaagaagaa actggagatc atacaatccc agaggggcca ggagtcggag tatgggaaca 1800 tcacctaccc tccggctttg aggagtgccc acgccaaagc ctcccgtacc tcgtccaaac 1860 acaaggagga ggtgtacgaa aacgtgcata gcaagaacaa gaaggaagag aaagtaaaga 1920 agcagcgatc ggcagacaag gagaagaaca aaggttctct caagaggaac atcagcctta 1980 ctccgtgcag aggcctccgc tgggcagaca gagacctgta gtccacacca cccccatctt 2040 gttgtaattt aagtgaccgt ggtcctctga acctgtatat ggctcagcaa gcctcaggga 2100 gagtcagacc cttctcttct tgtaaataaa gcccctggac aactgtgtaa aaaaaaaaaa 2160 aaaaaaaaaa ctcgag 2176 <210> SEQ ID NO 97 <211> LENGTH: 613 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 97 Met Leu Ser Arg Gly Trp Phe His Arg Asp Leu Ser Gly Pro Asp Ala 1 5 10 15 Glu Thr Leu Leu Lys Gly Arg Gly Val Pro Gly Ser Phe Leu Ala Arg 20 25 30 Pro Ser Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Asp 35 40 45 Asp Gln Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp 50 55 60 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Ser Thr Glu Leu Val Glu Tyr 65 70 75 80 Tyr Thr Gln Gln Gln Gly Ile Leu Gln Asp Arg Asp Gly Thr Ile Ile 85 90 95 His Leu Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp 100 105 110 Tyr His Gly His Met Ser Gly Gly Gln Ala Glu Ser Leu Leu Gln Ala 115 120 125 Lys Gly Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro 130 135 140 Gly Asp Phe Val Leu Ser Val Leu Asn Asp Gln Pro Lys Ala Ala Pro 145 150 155 160 Gly Ser Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly 165 170 175 Arg Tyr Thr Val Gly Gly Ser Glu Thr Phe Asp Ser Leu Thr Asp Leu 180 185 190 Val Glu His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe 195 200 205 Val Tyr Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val Asn Ala Ala Asp 210 215 220 Ile Glu Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Glu Ser Glu Asp 225 230 235 240 Thr Ala Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Leu Gln Lys Gln 245 250 255 Glu Ala Lys Asn Leu His Gln Arg Leu Glu Gly Gln Arg Pro Glu Asn 260 265 270 Lys Ser Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe Asp His Ser Arg 275 280 285 Val Ile Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Ser Asp Tyr Ile 290 295 300 Asn Ala Asn Tyr Val Lys Asn Gln Leu Leu Gly Pro Asp Glu Asn Ser 305 310 315 320 Lys Thr Tyr Ile Ala Ser Gln Gly Cys Leu Asp Ala Thr Val Asn Asp 325 330 335 Phe Trp Gln Met Ala Trp Gln Glu Asn Thr Arg Val Ile Val Met Thr 340 345 350 Thr Arg Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pro Tyr Trp Pro 355 360 365 Glu Val Gly Thr Gln Arg Val Tyr Gly Leu Tyr Ser Val Thr Asn Cys 370 375 380 Lys Glu His Asp Thr Ala Glu Tyr Lys Leu Arg Thr Leu Gln Ile Ser 385 390 395 400 Pro Leu Asp Asn Gly Asp Leu Val Arg Glu Ile Trp His Tyr Gln Tyr 405 410 415 Leu Ser Trp Pro Asp His Gly Val Pro Ser Glu Pro Gly Gly Val Leu 420 425 430 Ser Phe Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Leu Pro His Ala 435 440 445 Gly Pro Ile Ile Val His Cys Ser Ala Gly Ile Gly Arg Thr Gly Thr 450 455 460 Ile Ile Val Ile Asp Met Leu Met Glu Ser Val Ser Thr Lys Gly Leu 465 470 475 480 Asp Cys Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Val Arg Ala Gln 485 490 495 Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Phe Ile Tyr Val 500 505 510 Ala Ile Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Leu Glu Ile Ile 515 520 525 Gln Ser Gln Arg Gly Gln Glu Ser Glu Tyr Gly Asn Ile Thr Tyr Pro 530 535 540 Pro Ala Leu Arg Ser Ala His Ala Lys Ala Ser Arg Thr Ser Ser Lys 545 550 555 560 His Lys Glu Glu Val Tyr Glu Asn Val His Ser Lys Asn Lys Lys Glu 565 570 575 Glu Lys Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Lys Asn Lys Gly 580 585 590 Ser Leu Lys Arg Asn Ile Ser Leu Thr Pro Cys Arg Gly Leu Arg Trp 595 600 605 Ala Asp Arg Asp Leu 610 <210> SEQ ID NO 98 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Unique signature sequence motif found within conserved domain <220> FEATURE: <221> NAME/KEY: VARIANT <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa = Ile or Val <220> FEATURE: <221> NAME/KEY: VARIANT <222> LOCATION: 4, 7, 8 <223> OTHER INFORMATION: Xaa = Any Amino Acid <220> FEATURE: <221> NAME/KEY: VARIANT <222> LOCATION: 10 <223> OTHER INFORMATION: Xaa = Ser or Thr <400> SEQUENCE: 98 Xaa His Cys Xaa Ala Gly Xaa Xaa Arg Xaa Gly 1 5 10 

What is claimed is:
 1. A method for identifying a protein tyrosine phosphatase that is reversibly oxidized in a cell, comprising: contacting a biological sample comprising a cell that comprises at least one protein tyrosine phosphatase with a stimulus under conditions and for a time sufficient to induce reversible oxidation of at least one protein tyrosine phosphatase in the cell; isolating anaerobically the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and determining under reducing conditions a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is reversibly oxidized in a cell.
 2. The method of claim 1 wherein the protein tyrosine phosphatase is selected from the group consisting of SHP-2, PTP1B, and TC45.
 3. The method of claim 1 wherein the protein tyrosine phosphatase is selected from the group consisting of PTP1B, PTP-PEST, PTPγ, LAR, MKP-1, CRYPα, PTPcryp2, DEP-1, SAP1, PCPTP1, PTPSL, STEP, HePTP, PTPIA2, PTPNP, PTPNE6, PTPμ, PTPX1, PTPX10, SHP-1, SHP-2, PTPBEM1, PTPBEM2, PTPBYP, PTPesp, PTPoc, PTP-PEZ, PTP-MEG1, MEG2, LC-PTP, TC-PTP, TC45, CD45, LAR, cdc14, RPTP-α, RPTP-ε, RKPTP, LyPTP, PEP, BDP1, PTP20, PTPK1, PTPS31, PTPGMC, GLEPP1, OSTPTP, PTPtep, PTPRL10, PTP2E, PTPD1, PTPD2, PTP36, PTPBAS, PTPBL, BTPBA14, PTPTyp, HDPTP, PTPTD14, PTPα, PTPβ, PTPδ, PTPε, PTPκ, PTPλ, PTPμ, PTPρ, PTPψ, PTPφ, PTPζ, PTPNU3 and PTPH1.
 4. The method of claim 1 wherein the protein tyrosine phosphatase is a protein tyrosine phosphatase as presented in FIG.
 8. 5. The method of claim 1 wherein the protein tyrosine phosphatase is a dual specificity phosphatase.
 6. The method of claim 1 wherein the protein tyrosine phosphatase substrate comprises phosphorylated poly-(4:1)-Glu-Tyr.
 7. The method of claim 6 wherein the phosphorylated poly-(4:1)-Glu-Tyr comprises ³²P.
 8. The method of claim 1 wherein the detectably labeled protein tyrosine phosphatase substrate comprises a reporter molecule selected from the group consisting of a fluorophore, a radionuclide, a chemiluminescent agent, an enzyme, an immunologically detectable epitope and a chromaphore.
 9. The method of claim 8 wherein the fluorophore is selected from the group consisting of fluorescein, rhodamine, Texas Red, AlexaFluor-594, AlexaFluor-488, Oregon Green, BODIPY-FL and Cy-5.
 10. The method of claim 1 wherein the protein tyrosine phosphatase substrate comprises a polypeptide sequence derived from a protein selected from the group consisting of PDGF receptor, VCP, p130^(cas), EGF receptor, p210 bcr:abl, MAP kinase, Shc, insulin receptor, lck, T cell receptor zeta chain, and reduced and carboxyamidomethylated and maleylated lysozyme (RCML).
 11. The method of claim 1 wherein the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is an alkylating agent.
 12. The method of claim 1 wherein the sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is selected from the group consisting of iodoacetamide, iodoacetic acid, arsenic oxide, maleimide analog, haloacetimido analog, 4-vinylpyrimidine analog and N-ethylmaleimide.
 13. The method of claim 1 wherein the cell is a mammalian cell.
 14. The method of claim 13 wherein the mammalian cell is derived from a cell line.
 15. The method of claim 14 wherein the cell line is selected from the group consisting of Rat-1 fibroblasts, COS cells, CHO cells and HEK-293 cells.
 16. The method of claim 1 wherein the step of isolating the protein tyrosine phosphatase comprises cell lysis.
 17. The method of claim 16 wherein the step of isolating further comprises gel electrophoresis of the protein tyrosine phosphatase.
 18. The method of claim 17 wherein the step of isolating further comprises electrophoresis of the protein tyrosine phosphatase in a gel comprising the detectably labeled protein tyrosine phosphatase substrate.
 19. The method of claim 16 wherein the step of isolating further comprises detecting the protein tyrosine phosphatase with an antibody that specifically binds to the phosphatase.
 20. The method of claim 1 wherein the stimulus increases reactive oxygen species in the sample.
 21. The method of claim 1 wherein the stimulus is selected from the group consisting of a cytokine, a growth factor, a hormone, a cell stressor and a peptide.
 22. The method of claim 21 wherein the cell stressor is selected from the group consisting of a source of ROS and ultraviolet light.
 23. The method of claim 1 wherein the stimulus is selected from the group consisting of PDGF, EGF, bFGF, insulin, GM-CSF, TGF-β1, IL-1, IL-3, IFN-γ, TNF-α, PHA, AT-2, thrombin, thyrotropin, parathyroid hormone, LPA, sphingosine-1-phosphate, serotonin, endothelin, acetylcholine, platelet activating factor, bradykinin and G-CSF.
 24. A method for identifying a protein tyrosine phosphatase that is reversibly modified by a PTP active site-binding agent in a cell, comprising: contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine with a biological sample comprising a cell that comprises at least one protein tyrosine phosphatase; isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine, a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is reversibly modified by a PTP active site-binding agent in a cell.
 25. The method of claim 24 wherein the step of isolating is performed anaerobically.
 26. The method of claim 24 wherein the PTP active site-binding agent is selected from the group consisting of an agent that covalently binds to the PTP active site and an agent that non-covalently binds to the PTP active site.
 27. The method of claim 24 wherein the PTP active site-binding agent is selected from the group consisting of a sulfonated compound and a vanadate compound.
 28. The method of claim 24 wherein the PTP active site-binding agent covalently and reversibly modifies a sulfhydryl group of a PTP active site invariant cysteine.
 29. The method of claim 28 wherein the step of determining comprises reversing a covalent modification of a sulfhydryl group of a PTP active site invariant cysteine.
 30. The method of claim 29 wherein the step of reversing comprises contacting the PTP with a reducing agent.
 31. The method of claim 30 wherein the reducing agent is selected from the group consisting of dithiothreitol, dithioerythritol, and 2-mercaptoethanol.
 32. The method of claim 24 wherein the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is selected from the group consisting of iodoacetamide, iodoacetic acid, arsenic oxide, maleimide analog, haloacetimido analog, 4-vinylpyrimidine analog, and N-ethylmaleimide.
 33. A method for identifying a protein tyrosine phosphatase that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising: contacting a biological sample comprising a cell that comprises at least one protein tyrosine phosphatase with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a protein tyrosine phosphatase active site invariant cysteine from modification; isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the protein tyrosine phosphatase active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is a reversibly modified component of an inducible biological signaling pathway in a cell.
 34. The method of claim 33 wherein the step of isolating is performed anaerobically.
 35. The method of claim 33 wherein the sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine is selected from the group consisting of iodoacetamide, iodoacetic acid, arsenic oxide, maleimide analog, haloacetimido analog, 4-vinylpyrimidine analog, and N-ethylmaleimide.
 36. A method for identifying an agent that alters an inducible biological signaling pathway, comprising: (a) identifying a protein tyrosine phosphatase that is reversibly oxidized in a cell according to a method comprising: (i) contacting a first biological sample comprising a cell that comprises at least one protein tyrosine phosphatase with a stimulus under conditions and for a time sufficient to induce reversible oxidation of at least one protein tyrosine phosphatase in the cell; (ii) isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein detectable substrate dephosphorylation indicates that an active protein tyrosine phosphatase is present, and therefrom identifying a protein tyrosine phosphatase that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises the PTP that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of the PTP; (c) isolating the protein tyrosine phosphatase in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a protein tyrosine phosphatase active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled protein tyrosine phosphatase substrate by the protein tyrosine phosphatase, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, and wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway.
 37. The method of claim 36 wherein the step of isolating in the method recited in (a) is performed anaerobically.
 38. The method of claim 36 wherein the step of isolating recited in (c) is performed anaerobically.
 39. A method for identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is reversibly oxidized in a cell, comprising: contacting a biological sample comprising a cell that comprises SHP-2 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of SHP-2 in the cell; isolating anaerobically SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and determining under reducing conditions a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is reversibly oxidized in a cell.
 40. A method for identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is reversibly oxidized in a cell, comprising: contacting a biological sample comprising a cell that comprises PTP1B with a stimulus under conditions and for a time sufficient to induce reversible oxidation of PTP1B in the cell; isolating anaerobically PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and determining under reducing conditions a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and 12, and wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is reversibly oxidized in a cell.
 41. A method for identifying a TC45 protein tyrosine phosphatase (TC45) that is reversibly oxidized in a cell, comprising: contacting a biological sample comprising a cell that comprises TC45 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of TC45 in the cell; isolating anaerobically TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; and determining under reducing conditions a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, and wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is reversibly oxidized in a cell.
 42. A method for identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is reversibly modified by a PTP active site-binding agent in a cell, comprising: contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine with a biological sample comprising a cell that comprises SHP-2; isolating SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a SHP-2 active site invariant cysteine, a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is reversibly modified by a PTP active site-binding agent in a cell.
 43. A method for identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is reversibly modified by a PTP active site-binding agent in a cell, comprising: contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine with a biological sample comprising a cell that comprises PTP1B; isolating PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a PTP1B active site invariant cysteine, a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and 12, and wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is reversibly modified by a PTP active site-binding agent in a cell.
 44. A method for identifying a TC45 protein tyrosine phosphatase (TC45) that is reversibly modified by a PTP active site-binding agent in a cell, comprising: contacting a PTP active site-binding agent that is capable of reversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine with a biological sample comprising a cell that comprises TC45; isolating TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; and determining, under conditions that are capable of reversing a reversible modification of a sulfhydryl group of a TC45 active site invariant cysteine, a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, and wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is reversibly modified by a PTP active site-binding agent in a cell.
 45. A method for identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising: contacting a biological sample comprising a cell that comprises SHP-2 with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a SHP-2 active site invariant cysteine from modification; isolating the SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the SHP-2 active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, and wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is a reversibly modified component of an inducible biological signaling pathway in a cell.
 46. A method for identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising: contacting a biological sample comprising a cell that comprises PTP1B with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a PTP1B active site invariant cysteine from modification; isolating the PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the PTP1B active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and 12, and wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is a reversibly modified component of an inducible biological signaling pathway in a cell.
 47. A method for identifying a TC45 protein tyrosine phosphatase (TC45) that is a reversibly modified component of an inducible biological signaling pathway in a cell, comprising: contacting a biological sample comprising a cell that comprises TC45 with a stimulus that induces a biological signaling pathway under conditions and for a time sufficient to induce the biological signaling pathway and thereby reversibly protect a TC45 active site invariant cysteine from modification; isolating the TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; and determining, under conditions that reverse the reversible protection of the TC45 active site invariant cysteine from modification, a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, and wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is a reversibly modified component of an inducible biological signaling pathway in a cell.
 48. A method for identifying an agent that alters an inducible biological signaling pathway, comprising: (a) identifying a SHP-2 protein tyrosine phosphatase (SHP-2) that is reversibly oxidized in a cell according to a method comprising: (i) contacting a first biological sample comprising a cell that comprises SHP-2 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of SHP-2 in the cell; (ii) isolating SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein detectable substrate dephosphorylation indicates that an active SHP-2 is present, and therefrom identifying a SHP-2 that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises SHP-2 that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of SHP-2; (c) isolating SHP-2 in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a SHP-2 active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled SHP-2 substrate by SHP-2, wherein SHP-2 comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 14, 16, 26, 28, 30, and 32, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway.
 49. A method for identifying an agent that alters an inducible biological signaling pathway, comprising: (a) identifying a PTP1B protein tyrosine phosphatase (PTP1B) that is reversibly oxidized in a cell according to a method comprising: (i) contacting a first biological sample comprising a cell that comprises PTP1B with a stimulus under conditions and for a time sufficient to induce reversible oxidation of PTP1B in the cell; (ii) isolating PTP1B in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a PTP1B active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein detectable substrate dephosphorylation indicates that an active PTP1B is present, and therefrom identifying a PTP1B that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises PTP1B that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of PTP1B; (c) isolating PTP1B in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a PTP1B active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled PTP1B substrate by PTP1B, wherein PTP1B comprises a polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 2, 4, 6, 8, 10, and 12, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, and wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway.
 50. A method for identifying an agent that alters an inducible biological signaling pathway, comprising: (a) identifying a TC45 protein tyrosine phosphatase (TC45) that is reversibly oxidized in a cell according to a method comprising: (i) contacting a first biological sample comprising a cell that comprises TC45 with a stimulus under conditions and for a time sufficient to induce reversible oxidation of TC45 in the cell; (ii) isolating TC45 in the presence of a sulfhydryl-reactive agent that is capable of irreversibly modifying a sulfhydryl group of a TC45 active site invariant cysteine; (iii) determining under reducing conditions a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein detectable substrate dephosphorylation indicates that an active TC45 is present, and therefrom identifying a TC45 that is reversibly oxidized in a cell; (b) contacting, in the presence and absence of a candidate agent, a second biological sample comprising a cell that comprises TC45 that is reversibly oxidized as identified according to the method of (a) with the stimulus under conditions and for a time sufficient to induce reversible oxidation of TC45; (c) isolating TC45 in the presence of a sulfhydryl-reactive agent that is capable of covalently modifying a sulfhydryl group of a TC45 active site invariant cysteine; and (d) determining under reducing conditions a level of dephosphorylation of a detectably labeled TC45 substrate by TC45, wherein TC45 comprises a polypeptide comprising an amino acid sequence set forth in NM_(—)080422, wherein a level of substrate dephosphorylation that is decreased when the second sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is an inhibitor of an inducible biological signaling pathway, and wherein a level of substrate dephosphorylation that is increased when the sample is contacted with the stimulus in the presence of the candidate agent relative to the level of substrate dephosphorylation when the sample is contacted with the stimulus in the absence of the agent indicates that the agent is a potentiator of an inducible biological signaling pathway. 